Malignant Hyperthermia Susceptibility

Pharmacogenetics of excitation–contraction coupling in skeletal muscle: RYR1, CACNA1S and STAC3, with RYR1- and STAC3-associated myopathies.

Literature and regulatory information updated: 6 October 2026.

0. Initial Reference Table

1. Introduction

Malignant hyperthermia occupies a distinctive position among genetic diseases: in most carriers, no apparent disease exists until a drug routinely used in anaesthesia encounters an inherited muscular predisposition. It is therefore simultaneously an anaesthetic emergency, a pharmacogenetic condition with a strong-level recommendation and an entry point to a spectrum of myopathies ranging from a hypotonic child with scoliosis to an adult with cramps and exertional rhabdomyolysis. The geneticist is called upon before a relative's surgery, after a crisis, following a secondary finding on exome testing or during investigation of a congenital myopathy [1, 14].

The foundational report is the letter by Denborough and Lovell published in the Lancet in 1960, entitled «Anaesthetic deaths in a family», followed in 1962 by an article with the same title in the British Journal of Anaesthesia [18, 19]. In 1973, King and Denborough described anaesthesia-induced malignant hyperpyrexia in children; King-Denborough syndrome, first described that year, is characterised by the triad of dysmorphism, myopathy and malignant hyperthermia susceptibility [20, 21]. The therapeutic basis was established experimentally by Harrison in 1975, demonstrating in susceptible pigs that dantrolene sodium terminated the halothane-triggered syndrome and prevented its onset [22]. In 1982, the multicentre study by Kolb and colleagues, involving anaesthetists from 65 institutions, documented recovery without sequelae in all eleven patients with unequivocal or probable MH treated according to the protocol, in whom a mean intravenous dantrolene dose of 2.5 mg/kg produced clinical and biochemical changes suggestive of reduced cellular metabolism [23].

Molecular identification followed in 1990, when MacLennan and colleagues demonstrated, in a linkage study of families with MH, cosegregation of the phenotype with ryanodine receptor gene markers (lod score of 4.20 at zero centimorgans), and McCarthy and colleagues located the susceptibility locus at 19q12-13.2 [24, 25]. In 1991, Fujii and colleagues identified a point mutation in the porcine skeletal muscle ryanodine receptor gene, correlated with MH in five lean pig breeds, and Gillard and colleagues found the corresponding substitution, arginine 614 to cysteine, cosegregating with the phenotype in only one of 35 human families studied — a proportion already anticipating the genetic heterogeneity now recognised [26, 27]. The second confirmed locus emerged in 1997 with Monnier and colleagues' description of a variant in the α1S subunit of the L-type calcium channel [28]. The third, STAC3, was identified in 2013 by Horstick and colleagues through a zebrafish screen, simultaneously explaining Native American myopathy and revealing a new component of excitation–contraction coupling [29].

The history of RYR1-associated myopathies developed in parallel. In 1956, Magee and Shy published a description of «a new congenital non-progressive myopathy» [30]. In central core disease, a Japanese series of 27 unrelated patients, with sequencing of all 106 RYR1 exons, identified variants in 25 (93%) [31]. The accumulation of RYR1-associated phenotypes led Lawal and colleagues, in 2020, to propose a unified nomenclature of «RYR1-related disorders», whose spectrum includes malignant hyperthermia susceptibility, congenital myopathies, exertional rhabdomyolysis and lethal multiple pterygium syndrome [13]. This integration has immediate practical consequences: assessment of a patient with an RYR1 variant requires deciding, case by case, whether a pharmacogenetic trait, a myopathy, both or neither is present [14, 32].

2. Molecular Genetics and Pathophysiology

2.1. The triad and excitation–contraction coupling

Intracellular calcium in skeletal muscle is controlled through storage, release and reuptake in the sarcoplasmic reticulum. Ryanodine receptor type 1, encoded by RYR1, forms the calcium release channel in the terminal portion of the reticulum, adjacent to the transverse tubule membrane. This three-membrane structure — two terminal reticulum cisternae separated by a transverse tubule — is called the triad. During excitation–contraction coupling, the action potential propagates along the surface membrane and transverse tubules; depolarisation activates the dihydropyridine receptors encoded by CACNA1S, which trigger opening of adjacent RYR1 channels. The adaptor protein encoded by STAC3 binds the dihydropyridine receptor and is required for depolarisation to effectively open RYR1 channels. The three genes associated with malignant hyperthermia therefore control the same physiological step [1, 29].

In MHS-associated variants, the common outcome is increased sensitivity of the RYR1 channel to its activators. Therapeutic concentrations of volatile anaesthetics and suxamethonium do not open normal channels; in carriers, they open them directly. This is followed by uncontrolled calcium release, sustained contracture, glycogenolysis and activation of cellular metabolism, with excessive heat and lactate production, high oxygen consumption and high carbon dioxide production. Cell membrane injury caused by contracture releases creatine kinase and potassium into the circulation, explaining, respectively, rhabdomyolysis with renal risk and hyperkalaemic arrhythmias. Dantrolene sodium inhibits calcium release and leakage through RYR1 and reverses this process [1].

In RYR1-associated myopathies, the defect differs from that of isolated MHS: impaired excitation–contraction coupling predominates, with reduced calcium release or chronic leakage and, in recessive forms, reduced RYR1 protein itself. Analysis of biopsies from seventeen people with RYR1-related myopathy documented pathological reticular calcium leakage and increased activity of calcium-dependent proteases, normalised ex vivo by a channel-stabilising compound [33]. This mechanistic dissociation supports the explicit GeneReviews statement that a variant causing myopathy may not cause malignant hyperthermia susceptibility, and that a variant's relevance to MHS must be assessed separately from its relevance to myopathy [1].

2.2. Variants, nomenclature and correlations

The RYR1 reference transcript is NM_000540.3, confirmed as MANE Select, with protein NP_000531.2; GeneReviews describes it as «MANE Plus Clinical», a designation inconsistent with current annotation and corrected in this article through direct verification [1, 3]. NM_000069.3 (NP_000060.2) is used for CACNA1S and NM_145064.3 (NP_659501.1) for STAC3; older STAC3 literature cites NM_145064.2, a version for which validation returns an outdated-version warning, with the same protein consequence retained [3].

Conversions between nucleotide and protein nomenclature and genomic coordinates in this table were obtained through transcript validation and consultation of classifications in a public database, rather than manual calculation [3, 34].

The EMHG diagnostic variant list, accessed in October 2026, contains eighty-four RYR1 variants — fifty-six classified as pathogenic and twenty-eight as likely pathogenic — and two CACNA1S variants. The list has a change log dating from May 2025 and received, in March 2026, one new variant classified as pathogenic and five reclassifications, four from uncertain significance [35]. This dynamic is relevant to practice: the 2019 CPIC guideline was based on a snapshot of forty-eight RYR1 variants and two CACNA1S variants, so a variant absent from the CPIC list may now appear on the EMHG list [12, 35].

The ClinGen Variant Curation Expert Panel adapted the American College of Medical Genetics and Genomics and Association for Molecular Pathology criteria to the RYR1–malignant hyperthermia pair: seven criteria were adopted unchanged, nine with gene-specific modifications and ten abandoned, with quantitative calibration of in silico prediction and critical-domain location criteria [41, 42]. Subsequent classification of two hundred and fifty-one variants produced forty-two pathogenic or likely pathogenic, sixteen benign or likely benign and one hundred and ninety-three of uncertain significance, the predominant cause of uncertain classifications being insufficient evidence for pathogenicity rather than evidence against it; only thirteen variants had usable functional data [8]. In 2025, a caffeine-induced calcium release assay was formally calibrated using variants of known classification, obtaining a positive likelihood ratio of 12.14:1 and enabling use of the functional criterion at moderate strength; two of five variants of uncertain significance were reclassified as likely benign [43].

The 2025 European diagnostic guideline describes the coexistence of two curation systems derived from the ACMG/AMP model: the EMHG scoring matrix, agreed in 2022 with stricter criteria to avoid false benign classifications, and the ClinGen expert panel's Bayesian system. Both had been applied, at the date of the guideline, to 351 RYR1 variants, of which 72 were classified as pathogenic or likely pathogenic by the EMHG matrix and can be used to indicate increased risk; functional characterisation remains a key criterion for pathogenic classification in this matrix. For new variants, the EMHG recommends its own matrix rather than the ClinGen panel system, because the latter does not necessarily require functional analysis to classify a variant as pathogenic. The guideline also accepts that, when functional characterisation is performed in genetically manipulated heterologous or homologous expression systems, the variant no longer needs to have been described in more than one family, and retains two CACNA1S variants with functional evidence consistent with pathogenicity [9]. The figure of 72 variants refers to the guideline text; the regularly updated online list contained 84 RYR1 variants when accessed in October 2026 [9, 35].

Genotype–phenotype correlations remain limited. Stronger contractures and shorter response times to caffeine have been described in carriers of RYR1 variants than in carriers of CACNA1S or STAC3 variants, and no clinically useful correlations have been identified for STAC3 [1]. Historical data indicated that MHS-associated variants cluster in the hydrophilic N-terminal and central portions of the protein, whereas substitutions associated with central core disease lie mainly in the pore-forming region; this pattern supported the notion of two preferential clusters, but never allowed inheritance mode to be predicted from variant location [44, 45]. The expert panel treated critical-domain location as a moderate-strength criterion, with an odds ratio of 24:1, formalising the historical observation without converting it into a deterministic rule [41].

An additional caution concerns technical coverage: some exome capture reagents have reduced coverage of RYR1 exon 91, a guanine- and cytosine-rich region including codons 4209 to 4479 and two likely pathogenic variants, so a negative result may arise from insufficient sequencing depth [1, 8].

2.3. Unresolved heterogeneity and allelic diseases

Up to 40% of people with confirmed MHS have no identified variant in any of the three genes. Linkage studies indicated 17q11.2-q24, 3q13.1, 5p and 7q21-q22, but no additional gene has been confirmed [1]. The world's largest phenotyped cohort, in the United Kingdom, confirmed susceptibility in 795 independent families, with deoxyribonucleic acid samples available in 722; it found potentially pathogenic variants in 555 families and estimated that susceptibility unexplained by RYR1, CACNA1S or STAC3 occurs in 14 to 23% of families. In this cohort, twenty-five recurrent RYR1 variants and one CACNA1S variant, previously unclassified, were significantly overrepresented compared with a database of variants in low-risk populations, and genotype–phenotype discordance occurred in 86 of 328 families suitable for segregation analysis [46].

Allelic diseases determine anaesthetic management and counselling and are the reason this article integrates RYR1-associated myopathies.

Statin exposure warrants separate mention: RYR1 variants may contribute to genetic risk of nonanaesthetic myopathy, including statin-induced myopathy, and the CPIC guideline notes evidence that some variants on the EMHG list, including c.1840C>T, may increase rhabdomyolysis risk in people taking cholesterol synthesis inhibitors [1, 12].

3. Clinical Spectrum and Manifestations by System

3.1. The acute reaction

Manifestations follow exposure to potent volatile anaesthetics, alone or with suxamethonium. In almost all cases, the first signs appear in the operating theatre; however, the reaction may begin in the early postoperative period, usually within the first hour of recovery. The classic presentation begins with tachycardia, a rapid rise in expired carbon dioxide and tachypnoea — the latter rarely recognised because most patients are under neuromuscular blockade. This is followed by increased blood pressure, frequently with ventricular arrhythmias induced by sympathetic stimulation resulting from hypercapnia, hyperkalaemia and catecholamine release. Rigidity or increased muscle tone and a rise in body temperature at a rate of 1 to 2 °C every five minutes then become evident [1].

At the same time, the circuit's carbon dioxide absorbent becomes warm to the touch through the exothermic reaction with exhaled carbon dioxide. Skin mottling, sweating and, rarely, cyanosis may be observed. Blood gas analysis usually shows hypercapnia with a carbon dioxide partial pressure above 60 mmHg and mixed acidosis, without oxygen desaturation; an increase in expired carbon dioxide above 55 mmHg is one of the earliest signs, but vigorous mechanical hyperventilation may prevent hypercapnia and delay diagnosis. A mixed venous sample demonstrates carbon dioxide retention and metabolic acidosis even more markedly. Hyperkalaemia, hypercalcaemia, lactic acidaemia and myoglobinuria are characteristic but not constant. Serum creatine kinase frequently exceeds 20,000 units per litre within the first 12 to 24 hours [1].

The EMHG guideline divides signs into early and late, a distinction of operational value in the operating theatre. Early signs are inappropriately high carbon dioxide production, increased oxygen consumption, mixed acidosis, profuse sweating with mottling, inappropriate heart rate increase, arrhythmias — particularly ventricular extrasystoles and bigeminy — unstable blood pressure, masseter spasm if suxamethonium was used, and generalised rigidity. Late signs are hyperkalaemia, rapid core temperature rise, marked elevation of creatine kinase and myoglobin, dark urine from myoglobinuria, severe arrhythmias with cardiac arrest and disseminated intravascular coagulation [5].

Variability is considerable, and early recognition with a rapid response may prevent several signs from appearing. Hyperthermia may be an initial sign, but lack of core temperature monitoring delays detection; skin measurement is frequently misleading during the crisis. Acidosis may be mild if the syndrome is treated promptly, and hyperCKaemia with rhabdomyolysis is more frequent when suxamethonium has been used, with rhabdomyolysis sometimes appearing only several hours later. Hyperkalaemia is uncommon when the reaction is detected and treated in time, but may develop remarkably rapidly [1]. In the North American registry series, with 286 very likely or almost certain episodes between 1987 and 2006, young men predominated (74.8%); only 6.5% had a family history of MH and 77 of 152 patients reported two or more previous uneventful general anaesthetics. Temperature abnormality was among the first three signs in 63.5% of cases, with a median maximum temperature of 39.1 °C; 78.6% had both muscular abnormalities and respiratory acidosis, but only 26.0% had metabolic acidosis [52].

A point influencing counselling is that the reaction does not necessarily occur with every exposure. Manifestations depend on genetic predisposition, trigger exposure dose and duration, and preoperative factors including intense exercise and fever. Susceptible individuals may have one or several uneventful anaesthetics and then develop a fulminant reaction to the same or another agent: absence of a previous reaction does not guarantee absence of a future reaction [1, 53].

3.2. Complications and recrudescence

Even with treatment and survival, the patient remains at risk of myoglobinuric renal failure, disseminated intravascular coagulation, compartment syndrome and recrudescence within the first 24 to 36 hours. In the North American registry, nonfatal complications occurred in 35% of patients; twelve of these complications included cardiac, renal or hepatic dysfunction, coma or altered consciousness, pulmonary oedema and disseminated intravascular coagulation. The probability of any complication increased 2.9-fold for each 2 °C rise in maximum temperature and 1.6-fold for each 30-minute delay in dantrolene administration [1, 52]. Twenty-one patients had haematological or neurological complications at temperatures below 41.6 °C, considered the critical human threshold [52].

Recrudescence was analysed in 308 patients with a clinical score of 20 or higher: it occurred in 63 (20%), with a mean interval of 13 hours after the initial reaction. Muscular body habitus, clinical score of 35 or higher, temperature rise and an interval exceeding 150 minutes between induction and reaction were associated with recrudescence; muscular body habitus, temperature rise and longer time to reaction remained significant in multivariable analysis [54]. GeneReviews gives a recrudescence probability of 25%, and the European dantrolene summary of product characteristics gives 10 to 15% [1, 55]. The 2020 European dantrolene guideline cites the 20% from the North American series but considers 10 to 15% a probably more realistic estimate, and associates recrudescence with more severe cases and reactions requiring higher initial doses, occurring within the first 24 hours after initial resolution [56]. These values should not be reconciled by arbitrarily selecting one.

Presentation outside hospital brings its own problems. Deaths have occurred when the episode began during ambulatory surgery, with probable causes including inadequate preparation — particularly absence of dantrolene — insufficient or unprepared staff and difficulties stabilising the patient before transfer. All units are advised to have a plan and conduct periodic simulations [1, 57].

3.3. Manifestations outside anaesthesia

The relationship between susceptibility, heat stress and exertional rhabdomyolysis is documented by clinical, genetic and animal-model studies. Of twelve young men with exercise-induced rhabdomyolysis, ten had positive contracture testing and three had MHS-associated RYR1 variants [1, 58]. Canadian data showed an RYR1 or CACNA1S variant in three of seventeen people with susceptibility and exertional rhabdomyolysis [59]. A retrospective review at five referral centres identified 41 people with susceptibility confirmed genetically or by contracture testing who had a history of intense exercise in the preceding 72 hours and/or fever above 37.5 °C before the triggering anaesthetic, suggesting, according to the authors, a link between intense exercise or preoperative fever and MH; in these cases, surgery for trauma or acute abdomen, emergency surgery and suxamethonium use were also more frequent than during previous uneventful anaesthetics [1, 53]. Viral illness, exercise in a hot environment and exercise combined with alcohol intake were identified as potential triggers [1, 36]. In six unrelated African American men with unexplained exertional rhabdomyolysis, subsequently diagnosed as susceptible by CHCT, three new RYR1 variants and two previously described in susceptible Caucasian individuals were found in five; the same study identified the p.Ala1352Gly variant (published designation, = NM_000540.3:c.4055C>G p.(Ala1352Gly)), previously associated with susceptibility, as a predominant polymorphism in people of African ancestry, highlighting the need to interpret variants across different population groups [37]. Despite these associations, exertional heat illness and exertional rhabdomyolysis have complex genetic heterogeneity and are not confined to RYR1 [1].

The consensus from the 276th European Neuromuscular Centre workshop proposed operational criteria for rhabdomyolysis: clinical symptoms with severe muscle swelling, weakness and/or myalgia; creatine kinase above 10,000 units per litre in the exertional form and above 5,000 in the nonexertional form; a peak between the first and fourth days with normalisation after one to two weeks of rest; and, if underlying neuromuscular disease exists, values five to ten times the patient's own baseline. Specific treatment should begin only if acute kidney injury risk is high, estimated using the McMahon score, and the RHABDO acronym was adopted to select individuals for genetic testing [60]. In a retrospective study of 122 patients genetically tested for rhabdomyolysis, a pathogenic or likely pathogenic variant was found in thirteen (11%), all with at least two acronym features; the positive predictive value of two or more features was 14% and the negative predictive value 100% in the sample studied [61].

The EMHG-commissioned narrative review of myopathic manifestations throughout adult life describes cramps, stiffness, myalgia, rhabdomyolysis and weakness in susceptible individuals without anaesthetic exposure, with highly variable age at onset, predominantly in adulthood; histopathology may show nonspecific changes suggesting RYR1 involvement, and the metabolic profile reflects altered muscle energy metabolism. These manifestations affect quality of life and impose functional limitations, so the authors recommend early counselling after diagnosis and multidisciplinary management [32]. A prospective longitudinal study of fifty participants, forty-three of whom completed all three assessments over one year, documented fatigue and impairment of sleep and rest, walking, activities of daily living and recreation, with lower quality of life, more pronounced in those reporting overt neuromuscular symptoms; anxiety and depression did not differ from controls [62].

3.4. Manifestations in associated myopathies

In congenital myopathies overall, common findings are delayed motor milestones, prominent facial weakness and ptosis, dolichocephaly, a long narrow face, high-arched palate, normal intelligence, generalised weakness predominantly proximal and affecting the girdles, and variable distal, axial and respiratory involvement; weakness tends to be stable or slowly progressive, with respiratory and bulbar weakness in the most severe cases [63]. Central core disease is described with an elongated face, high-arched palate, facial diplegia with preserved extraocular muscles, shoulder and pelvic girdle weakness, thoracic deformity, pes cavus, scoliosis and, in the severe form, neonatal hypotonia with respiratory failure; creatine kinase is usually normal [44, 63, 64]. Cardiac involvement in RYR1-, SELENON- and ACTA1-associated forms is rare, unlike congenital titinopathies, in which cardiac involvement affects approximately half of cases [64].

STAC3 myopathy has been quantitatively described. Among 44 reported individuals — 21 of Lumbee ancestry and 23 of other ancestries — hypotonia occurred in 41 of 41 with records, myopathic facies in 44 of 44, ptosis in 33 of 39, poor feeding in 29 of 40, congenital contractures in 35 of 43, spinal deformity in 31 of 39, short stature in 19 of 29, palatal abnormalities in 36 of 44 — including cleft palate in 25 — malignant hyperthermia in 19 of 44, respiratory impairment in 16 of 29 and cryptorchidism in 13 of 21 boys. Maximum motor ability among fifteen individuals of assessable age was independent walking in eleven, short-distance walking in two, running in one and independent sitting in one. Thirty-six per cent of affected individuals died by age 18; GeneReviews and the original series differ in presentation of this figure, which derives from the Lumbee cohort rather than a general population [4, 49]. All individuals with a reported MH episode survived, and the authors emphasise that the true susceptibility frequency is probably higher, as not all were exposed to a triggering anaesthetic [4].

4. Clinical Recognition and Warning Signs

Recognition relies on a pattern rather than an isolated sign. Any patient may develop a reaction during or shortly after an anaesthetic involving triggering agents, even after previous uneventful general anaesthetics [5]. In the operating theatre, unexplained hypercapnia combined with tachycardia and muscle rigidity, followed by a temperature rise, requires immediate treatment; waiting for fever is a clinical error, because temperature can be an early sign in almost two thirds of cases or appear late, and because delayed dantrolene administration measurably increases the likelihood of complications [5, 52].

Outside the theatre, warning signs prompting assessment are different. In its 2025 review, the EMHG groups the most common referral reasons into three categories. Clinical signs: suspected clinical MH reaction related to triggering-agent exposure; a blood relative with a confirmed or suspected clinical reaction; and a family history of unexplained perioperative death when trigger use cannot be excluded. Genetic findings: a variant in a gene, for example RYR1, that may increase clinical reaction risk. Other reasons: signs, symptoms or findings such as exertional or recurrent rhabdomyolysis, idiopathic hyperCKaemia and exertional heat stroke. The guideline does not set definitive acceptance criteria: the decision to investigate is made case by case by the diagnostic centre's MH specialist, explicitly encouraging collaboration between accredited laboratories and their advisory boards in difficult cases, and clinical events should be recorded in a standardised way in the anonymous EMHG registry [9]. The 2015 version listed more detailed criteria — for example, a reaction with initial signs during anaesthesia or within 60 minutes after its discontinuation, postoperative rhabdomyolysis after excluding other myopathies, exertional heat stroke requiring hospitalisation and myopathy with a rare potentially pathogenic RYR1 variant — replaced by this broader formulation in the 2025 review [9, 65].

The 2026 North American approach operationalises the same concepts with explicit thresholds for preanaesthetic use. It defines a personal history of MH as an adverse reaction triggered by a volatile agent and/or suxamethonium validated by experts, positive contracture testing or a diagnostic variant. It defines family history as a three-generation pedigree. It defines hyperCKaemia as persistently elevated creatine kinase, two or more standard deviations above the expected population mean, on at least two occasions, excluding severe trauma, myopathy and the period immediately after intense exercise. For exertional heat illness it proposes a core temperature threshold of 40.5 °C or rhabdomyolysis with elevated creatine kinase associated with typically very intense exercise, and emphasises that these conditions should be distinguished from classic cramps, exhaustion and heat stroke associated with high ambient temperature [14].

The Larach clinical grading scale remains the most widely used probability tool. It weights respiratory acidosis (up to 15 points; expired carbon dioxide above 55 mmHg or partial pressure above 60 mmHg), cardiac involvement (3; unexplained sinus tachycardia, ventricular tachycardia or fibrillation), metabolic acidosis (10; base deficit above 8 mEq/L, pH below 7.25), muscle rigidity (15; generalised or severe masseter spasm), muscle breakdown (15; creatine kinase above 20,000 units per litre, cola-coloured urine, excess myoglobin, plasma potassium above 6 mEq/L), temperature increase (15; rapid rise above 38.8 °C), rapid reversal with dantrolene (5), elevated baseline creatine kinase (10) and family history consistent with dominant inheritance (15). The sum produces a raw score corresponding to six probability levels, from 0 («almost never») to 50 or more («almost certain») [1, 66].

The scale has explicit limitations. Not all findings can be measured in every case — arterial blood gases may be unavailable — and MH must be recognised and treated before all signs appear, mechanically lowering scores in well-treated cases [1]. In a series of true reactions, only 55.8% had a score of 35 or higher [14]. In the French cohort of 93 fully investigated patients at a referral centre between 1968 and 2020, a 45-point threshold had specificity of 90% (range 87 to 93%) and sensitivity of 59% (range 54 to 94%), performance similar to the original description; the triad of hyperthermia, hypercapnia and rigidity was present in 86% of the 49 susceptible patients [67]. Given this profile, the scale estimates probability and guides referral, rather than excluding diagnosis or determining treatment during an ongoing crisis.

One isolated sign warrants particular mention: masseter spasm after suxamethonium. In the Swedish registry, comprising 2,852 people from 544 families investigated since 1980, susceptibility was confirmed in 41% of index cases in which masseter spasm was the sole clinical sign [68]. GeneReviews considers severe masseter spasm accompanied by generalised rigidity, isolated spasm after suxamethonium, and limited spasm accompanied by rhabdomyolysis and/or hyperCKaemia definite indications for biopsy [1].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria for establishing the diagnosis

Susceptibility is considered established in a proband with a positive diagnostic contracture test or a heterozygous pathogenic or likely pathogenic variant in one of the three genes [1]. Two qualifications govern this formulation. First, molecular testing does not have 100% sensitivity: susceptibility cannot be excluded by absence of a pathogenic variant, in which case contracture testing should be performed at an accredited centre [1]. Second, pathogenicity assessment for isolated MHS must be distinguished from assessment for symptomatic myopathy, because the latter is a pleiotropic, genetically heterogeneous group, and a variant causing myopathy may not cause susceptibility [1].

The 2025 revision of the EMHG diagnostic guidelines, approved at the group's annual meeting in April 2025 and published in January 2026, was read in full for this version of the article, together with the August 2026 corrigendum, which merely adds an omitted name to the list of signatory group members (H. C. A. Silva, from the malignant hyperthermia centre at the Universidade Federal de São Paulo), without changing recommendations [9]. The revision introduces three elements directly affecting patient classification. The first is a consensus definition of clinical reaction, agreed in 2024: «malignant hyperthermia is a potentially fatal clinical reaction resulting from uncontrolled calcium release in skeletal muscle cells, triggered by potent inhalational anaesthetics and/or suxamethonium; clinical signs are characterised by a progressive hypermetabolic state, but may also include muscle rigidity and/or rhabdomyolysis». The reaction is now exclusively associated with triggering anaesthetic agents, to provide a uniform phenotype against which variant pathogenicity can be assessed; a suspected clinical reaction should be confirmed by IVCT or identification of a pathogenic or likely pathogenic MHS variant [9]. The second is the designation «MH genotype» (MHG): «the presence of a genetic variant classified as pathogenic or likely pathogenic for increased risk of developing MH under anaesthesia defines an MH genotype; carriers of this variant not classified as MHS by IVCT receive the diagnostic classification MHG». Information given to the patient is the same — increased MH risk under anaesthesia — but the scientific distinction between a positive IVCT (MHS) and positive molecular result (MHG) is maintained [9]. The third is reaffirmation that MHN status can be confirmed only by IVCT [9].

5.2. In vitro contracture testing

Since the mid-1970s, the reference test has been in vitro measurement of the contractile response of biopsied muscle to graded caffeine concentrations and the anaesthetic halothane. It is called the caffeine–halothane contracture test (CHCT) in North America and the in vitro contracture test (IVCT) in Europe and elsewhere; Japan uses a calcium-induced calcium release test, without established international standards [1].

The current European protocol is the 2025 revision, which simplified the 2015 version by excluding nonstandardised procedures and substances [9]. Biopsy is taken from the quadriceps, vastus medialis or lateralis, under local, regional or general anaesthesia; local anaesthetic solution must not be infiltrated or applied directly to the muscle, and all triggering agents are contraindicated. After weighing risks and benefits, biopsy and IVCT should not normally be performed in children younger than 10 years or weighing less than 30 kg, and protocol sensitivity and specificity have not been studied below age 4; the 2025 revision summarises the 2015 version as having added a minimum age of 10 years and minimum weight of 30 kg, but the 2015 text says otherwise: the minimum age for biopsy was 4 years, laboratories should not test children under 10 without relevant control data and could set minimum weight limits; 30 kg appeared only as an example, in the discussion, of some members' concerns about cosmetic and functional consequences of biopsy in low-weight children [9, 65]. The combined threshold of 10 years and 30 kg as a rule therefore comes from the 2025 version [9, 65]. Muscle may be dissected in vivo or removed en bloc for laboratory dissection and is immediately placed in precarboxygenated Krebs–Ringer solution of defined composition (NaCl 118.1; KCl 3.4; MgSO₄ 0.8; KH₂PO₄ 1.2; glucose 11.1; NaHCO₃ 25.0; CaCl₂ 2.5 mmol/L), with a maximum 10% deviation and pH 7.35 to 7.45 at 37 °C; it is transported at room temperature and kept carboxygenated, and time from biopsy to completion of testing should not exceed five hours. Assays are performed at 37 °C, with at least four tests, each on a fresh sample: two static cumulative caffeine tests and two static halothane tests, in separate baths for each agent; the dynamic halothane test, accepted in the 2015 version as an alternative to one static test, is now solely a research tool. Samples should be 20 to 25 mm long between loops, 2 to 3 mm thick and weigh 100 to 200 mg; optimal length is determined by progressive stretching under supramaximal electrical field stimulation (1 to 2 ms, 0.2 Hz, at 120% of initial intensity), with at least 15 minutes' stabilisation until baseline force varies by no more than 2 mN over 10 minutes. Caffeine is increased in steps of 0.5; 1.0; 1.5; 2.0; 3.0; 4.0 and 32 mmol/L, without washing between concentrations, and halothane is tested at 0.11; 0.22; 0.44 and, optionally, 0.66 mmol/L, equivalent to 0.5; 1.0; 2.0 and 3.0% by volume, with minimum exposure of three minutes at each concentration. The threshold is the lowest concentration producing an increase of at least 2 mN (0.2 g) relative to the lowest force reached, which does not necessarily coincide with the predrug force, and the maximum contracture at 2 mmol/L caffeine should also be reported [9].

Quality control requires viability demonstrated by twitches of at least 10 mN before drug application and, in the caffeine test, a response of at least 50 mN to 32 mmol/L at the end; bath halothane and caffeine concentrations should be verified regularly, ideally at least every six months, with a maximum accepted deviation of 10%. Candidate units should test sufficient control biopsies before beginning diagnostic activity, from healthy volunteers, amputations for localised nonsystemic and nonvascular disease, varicose vein surgery, brain-dead donors within the first 24 hours or fractures within the first 24 hours [9].

European laboratory classification distinguishes four categories: MHShc, with a caffeine threshold of 2.0 mmol/L or lower in at least one test and halothane threshold of 0.44 mmol/L or lower in at least one test; MHSh, with a halothane threshold of 0.44 mmol/L or lower in at least one test and caffeine threshold of 3 mmol/L or higher in all caffeine tests; MHSc, with a caffeine threshold of 2.0 mmol/L or lower and halothane threshold above 0.44 mmol/L in all halothane tests; and MHN, with a caffeine threshold of 3 mmol/L or higher in all caffeine tests and halothane threshold above 0.44 mmol/L in all halothane tests [9]. The North American protocol uses 3% halothane exposure, requires three muscle strips per drug and considers positive a contracture of 0.7 g or greater to halothane or 0.3 g or greater to 2.0 mmol/L caffeine, whereas the European version uses incremental exposure and two strips per drug [1, 9].

Test performance is described in ways that should not be conflated. GeneReviews gives sensitivity above 95% for both protocols and specificity generally between 80 and 97% [1]. Analysis of the North American registry, comparing 32 cases classified as «almost certain» by clinical criteria with 120 low-risk controls, obtained maximum sensitivity of 97% (confidence interval 84 to 100%) with specificity of 78% (69 to 85%) for a two-component criterion, concluding that the test cannot be used for screening [69]. The 2026 North American review cites sensitivity of 100% and specificity of 94% for IVCT and 97% and 78% for CHCT, values derived from different studies rather than direct comparison [14]. The 2025 European guideline recalls that the study aligning IVCT with the clinical scale estimated sensitivity of 99% and specificity of 94%, and that subsequent review of the only «almost certain» case with negative IVCT showed that the original clinical score was miscalculated, bringing the point estimate of sensitivity to 100% [9]. GeneReviews notes that some laboratories add ryanodine at 1.0 or 2.0 µmol/L or 4-chloro-m-cresol to clarify equivocal results; in the 2025 European revision, the dynamic halothane test and these additional agents may continue to be used in research but are not required for diagnosis [1, 9].

Practical limitations are decisive in strategy selection. The test requires approximately 2 g of muscle processed within five hours at a dedicated centre, as samples cannot be sent to another laboratory; it is not recommended below approximately 20 kg or age five years, or for diagnosis of neuroleptic malignant syndrome or serotonin syndrome [1]. The European threshold is more conservative: normally not before age 10 or below 30 kg [9]. Availability is uneven: there are three centres in North America according to GeneReviews, only two of which are publicly accessible — Toronto and Minneapolis — according to the 2026 North American review, which adds that the Maryland centre serves only military personnel and research participants, and fifteen accredited centres in Europe, Australia and New Zealand [1, 14]. Only approximately 4% of people with suspected susceptibility undergo CHCT [14]. Units following the EMHG protocol are located in Europe, South Africa, Brazil, Australia and New Zealand [17].

5.3. Genetic testing, indications and report limitations

Indications for molecular testing according to GeneReviews are a confirmed clinical episode, positive contracture test, high episode probability according to centre consultants or the clinical scale, a relative with positive contracture testing or a known causal variant, unexplained death with MH signs during or immediately after anaesthesia, and repeated exertional rhabdomyolysis and/or heat stroke [1].

The recommended first-line approach is a multigene panel including RYR1, CACNA1S, STAC3 and other genes of interest, with complete sequencing of the panel genes. Testing only the familial variant is explicitly discouraged, even in at-risk relatives, because it cannot detect a second variant segregating in the family. If gene-targeted testing identifies no variant in a person with positive contracture testing, exome or genome sequencing may be considered [1]. The 2025 European review agrees on methodology, but not on interpretation of a negative result. It considers high-throughput sequencing — targeted panel, exome or genome — the method of choice for primary screening, discourages RYR1 «hotspot» sequencing because it focuses on a small number of exons and may have underestimated relevant gene regions, and recognises that increasing numbers of classified variants allow more families to benefit from molecular diagnosis, through either familial-variant cascade screening or exon-targeted approaches [9]. It nevertheless maintains that genetic testing can only confirm increased risk and never exclude it: when referral follows a clinical reaction, genetics and IVCT should be considered together, and, in the absence of a pathogenic or likely pathogenic variant, the EMHG recommends IVCT to exclude increased risk in those with a personal or family history of MH, citing evidence of a biological basis for discordance between genotype and contracture phenotype. Without access to IVCT, genetic testing alone does not change the need for precautions; a negative result may falsely suggest negligible risk to patients and professionals, and the guideline acknowledges that it may be safer to consider the patient at risk and not test, although in the index case identification of a pathogenic or likely pathogenic variant confirms diagnosis and opens a genetic pathway for relatives [9]. The 2015 version already allowed predictive testing for the familial variant, noting discordance between contracture and genetics in approximately 5% of families studied [65]. The difference between the GeneReviews position (complete panel in all relatives) and the European position (familial-variant cascade possible, but exclusion only by IVCT) is relevant to counselling and should be explained to the patient rather than resolved by omitting either.

The laboratory report should include the gene, versioned transcript, Human Genome Variation Society nomenclature at nucleotide and protein levels, zygosity, classification according to American College of Medical Genetics and Genomics and Association for Molecular Pathology criteria — using the expert panel specification for RYR1 and malignant hyperthermia when applicable — and methodological limitations [41, 42]. For these genes, GeneReviews notes that some exome reagents have reduced coverage of RYR1 exon 91 and sequence analysis does not typically detect whole-exon deletions or duplications [1]. Large deletions or duplications of one or several exons have not been described in these three genes and are not expected given the gain-of-function mechanism [1]. Reclassification of variants of uncertain significance depends on additional evidence, particularly functional evidence — found by the expert panel for only 13 of the 251 variants it classified — and a validated functional assay contributes to classification with a defined strength, moderate for the caffeine-induced calcium release assay, rather than as standalone proof [8, 43].

The CPIC guideline assigns phenotype from genotype in only two categories. A person heterozygous for an EMHG-designated MH-causal variant in RYR1 or CACNA1S is classified as susceptible; a person negative for these variants is classified as having uncertain susceptibility, with the explicit qualification that a negative result does not eliminate possible susceptibility, as the genetic cause of approximately half of MH survivors with contracture-confirmed susceptibility remains unknown. The guideline also notes that people with biallelic RYR1 variants generally have recessive myopathies and should be treated according to standards for these disorders by consultants experienced in them, and recognises that a laboratory or clinician may conclude that a variant not assessed by the EMHG is pathogenic [12].

For STAC3, the CPIC guideline states that potent volatile agents and suxamethonium should be avoided in STAC3 myopathy, but that data are insufficient to determine whether a person with an STAC3 variant without the myopathy is susceptible [12]. The EMHG maintains the explicit position that, given scarce clinical information about the reported episodes, the almost complete absence of contracture confirmation and the lack of robust experimental evidence of an MHS-compatible phenotype, including STAC3 variants as diagnostic for susceptibility would be premature; it nevertheless recommends considering susceptibility when a rare homozygous or compound heterozygous variant associated with myopathy is identified, and providing trigger-free anaesthesia to anyone with a compatible phenotype [70]. GeneReviews, in turn, includes STAC3 among MHS genes with a contribution below 1% [1]. The article presents all three positions because this is the actual state of the evidence.

5.4. Algorithm and interpretation according to context

The 2025 European review presents two diagnostic pathways, in figures 1 and 2 of the article, consulted for this article, both qualified by the possibility of individual decisions about methods according to patient information and consent [9]. In the first, for individuals with a personal or family history of suspected MH, either genetics or IVCT may be the starting point: a pathogenic or likely pathogenic variant leads to MHG classification and advice of increased risk under anaesthesia; a variant of uncertain significance or absence of a variant leads to IVCT, whose MHShc, MHSh or MHSc result classifies the patient as MHS and whose MHN result classifies them as «not at risk of developing MH under anaesthesia». In the second, for an RYR1 variant found without a personal or family history of a clinical reaction, a pathogenic or likely pathogenic variant leads directly to MHG, and a variant of uncertain significance leads to IVCT. The guideline adds that, in families in which the variant was an incidental finding and there is no family history of clinical MH signs, relatives may be investigated and diagnosed solely by genetic testing [9].

In complicated cases, the EMHG asks that all available information be considered — clinical assessment, IVCT, genetics, muscle histopathology, serum biochemistry and other data — and encourages collaboration between accredited laboratories and their advisory boards. The guideline also emphasises that an MH reaction in the family significantly increases the pretest probability of susceptibility and must be distinguished from an incidental finding in risk assessment, and that variant classification is a dynamic process [9].

The 2026 North American approach structures preanaesthetic decision-making around three questions: does the patient have susceptibility or a previous reaction; does anyone in the family have susceptibility or a previous reaction; has the patient or a relative undergone genetic testing, and with what result? The underlying principle is that a genetic result is interpreted like any other diagnostic test, according to pretest probability. When pretest probability is low, as in population screening or a secondary finding, disease probability after a positive result is low and probability after a negative result is extraordinarily low [14].

The «high-range uncertain significance» category is defined by a score of 4 to 5 points in the point-based Bayesian adaptation of classification criteria, corresponding to pathogenicity probabilities of 68 to 86%, below the 6-point threshold for «likely pathogenic»; the authors emphasise that variant pathogenicity probability is not the same as the probability that a person has the disease [14]. The justification for lowering the reporting threshold relative to that recommended for all other diseases on the secondary findings list is explicit: post-test assessment is modest, the consequences of a reaction are devastating and avoiding triggering agents is relatively straightforward, so the authors accept that a majority identified through variants in this range will be false positives [14]. The authors themselves state that the recommendations are intended for North America, where contracture testing is practically inaccessible, rather than settings where testing is available, such as Europe and the United Kingdom [14]. This geographical boundary should be respected: applying the North American algorithm where IVCT exists, or European management where it does not, would produce inappropriate recommendations. The two approaches differ mainly for uncertain variants: the North American proposal treats the high range as susceptibility and considers that a relative without the familial variant and with only intermediate- or low-range variants has no risk above population level, whereas the European guideline assigns no clinical significance to any uncertain variant and refers risk exclusion to IVCT [9, 14].

Two findings quantify the problem of screening interpretation. In Geisinger's genomic screening programme, 152 participants received an actionable RYR1 variant result; 68 (44.7%) had anaesthetic records documenting triggering-agent exposure in at least one procedure. None received dantrolene or had recorded rigidity, myoglobinuria, hyperkalaemia, elevated creatine kinase, severe myalgia or dark urine. Of 120 possibly related findings — postoperative intensive care admissions, hyperthermia, blood gas measurements, hypercapnia or tachycardia — 112 (93.3%) were considered unlikely to be MH events and 8 (6.7%) had insufficient records to establish aetiology [71]. In Portugal and Brazil, equivalent programmes returning secondary findings with published anaesthetic follow-up were not identified in the sources consulted; this absence refers to the sources consulted and does not demonstrate absence of studies.

Finally, RYR1 and CACNA1S are on the American College of Medical Genetics and Genomics list of genes recommended for reporting secondary findings in clinical exome and genome sequencing, version 3.3 of 2025, associated with malignant hyperthermia and OMIM entries 145600 and 601887 [72]. Consequently, more people are likely to attend preanaesthetic consultations with a genetic result without personal or family history, and interpretation of such results has become routine practice [14].

6. Differential Diagnosis

The combination of hypercapnia, muscle rigidity, tachycardia, hyperthermia, metabolic acidosis and rhabdomyolysis during or shortly after anaesthesia is distinctive, but several conditions share elements of the presentation [1].

Among inherited muscle diseases, GeneReviews distinguishes those that mimic MH from those that cause it. CLCN1-related myotonia congenita and myotonic dystrophies types 1 and 2 may be associated, after suxamethonium, with muscle rigidity simulating MH; in dystrophinopathies, administration of suxamethonium or potent volatile agents carries increased risk of rhabdomyolysis and potentially fatal hyperkalaemia with cardiac arrest, termed anaesthesia-induced rhabdomyolysis and distinct from MH [1, 15]. Suxamethonium may cause rhabdomyolysis barely evident on physical examination in people with myotonic syndromes or dystrophinopathies, and perioperative rhabdomyolysis may occur in people taking cholesterol synthesis inhibitors [1].

The 2026 EMHG consensus on primary inherited muscle diseases reinforces this separation. It recalls that, for decades, patients with any myopathy were incorrectly considered at MH risk based on reports of perioperative hypermetabolic reactions, fever, hyperkalaemia, rhabdomyolysis or death, and that subsequent investigation clarified the mechanisms distinguishing MH from these nonspecific phenomena. It states that patients with myotonia have MH risk equivalent to the general population, although suxamethonium, anticholinesterases and hypothermia may trigger myotonic reactions that hamper ventilation. It proposes the term «perioperative rhabdomyolysis» rather than anaesthesia-induced rhabdomyolysis, accommodating factors such as positioning, nonanaesthetic drugs, fasting, inflammation and the surgical stress response, and offers criteria for differentiation in the acute phase: rapid expired carbon dioxide rise, unexplained mixed acidosis and other hypermetabolic signs — tachycardia, tachypnoea, temperature rise — suggest MH, whereas sudden cardiac arrest or cola-coloured urine suggest perioperative rhabdomyolysis. The distinction matters because the priority in perioperative rhabdomyolysis is maintaining cardiac output and lowering potassium, whereas in an MH crisis it is immediate dantrolene administration [73].

In the differential diagnosis of a hypotonic child with congenital myopathy, the Brazilian source systematises the entities to consider: congenital muscular dystrophy, with facial sparing, distal laxity in collagenopathies, leg hypertrophy in alpha-dystroglycanopathies, elevated creatine kinase and cranial MRI abnormalities; congenital myotonic dystrophy, in which the mother may be asymptomatic and maternal investigation is decisive, and whose biopsy may show central nuclei resembling X-linked centronuclear myopathy; metabolic myopathies, with organomegaly in Pompe disease, elevated lactate, acidosis, abnormal ammonia and organic acids, glycogen or lipid accumulation and ragged red fibres; congenital myasthenic syndromes, with ptosis, ophthalmoplegia and bulbar weakness, single-fibre studies and repetitive stimulation; spinal muscular atrophy, with tongue fasciculations, facial sparing and SMN1 testing; congenital hypomyelinating neuropathy, with sensory abnormalities and slow nerve conduction; and Prader-Willi syndrome, with bulbar weakness, growth deficiency and chromosome 15 methylation testing [63]. In STAC3 myopathy, the differential also includes MYMK-related Carey-Fineman-Ziter syndrome, with no documented susceptibility to date, and Moebius syndrome, in which restricted ocular abduction is mandatory [4].

Malignant hyperthermia is also mentioned as an occasional complication in several morphologically recognisable syndromes, which matters for the preoperative consultation: Noonan syndrome, Schwartz-Jampel syndrome — in which anaesthesia carries risk through difficult intubation and susceptibility — Larsen syndrome and multiple pterygium syndrome with malignant hyperthermia, characterised by scoliosis, torticollis, myopathic facies and cleft palate [74–79]. In the bone dysplasia atlas, malignant hyperthermia appears among the possible additional findings of Schwartz-Jampel syndrome, alongside kyphoscoliosis, carpal tunnel syndrome, a high-pitched voice and pectus carinatum [76]. In the metabolic field, COG7-CDG includes malignant hyperthermia among the features that distinguish it from COG6-CDG [80], and the long-chain mitochondrial fatty acid oxidation disorders, with the exception of CPT I deficiency, may present in infancy, even in the neonatal period, with cardiac arrest or hypotension, a picture easily mistaken for toxic shock or malignant hyperthermia [81]. It should be noted that these associations described in morphological atlases have a different level of evidence from entities with an established gene and mechanism, and that references to malignant hyperthermia in these settings do not necessarily correspond to episodes confirmed by contracture testing or genetics.

Among diagnoses that are not MH but require anaesthetic precautions, suxamethonium sensitivity due to pseudocholinesterase deficiency is the classic entity. Suxamethonium is metabolised in plasma by pseudocholinesterase, with neuromuscular blockade normally lasting less than five minutes. People homozygous or compound heterozygous for certain variants produce an enzyme with abnormal affinity and in reduced amounts, with prolonged blockade; artificial ventilation is required until resolution, usually approximately 90 minutes after suxamethonium and approximately five hours after mivacurium, with apnoea lasting up to three days in the most sensitive cases. Inheritance is recessive, with 25% sibling risk, and low-activity variants are defined by cholinesterase levels and the degree of inhibition by dibucaine, fluoride and propan-1-ol. Atypical variant frequency in Caucasian populations is 0.017, corresponding to a homozygote frequency of approximately 1 in 3,500. Cholinesterase levels also fall during pregnancy, liver disease and through other drugs, with a small clinical prolongation [47].

7. Treatments and Risk Management Strategies

7.1. Crisis treatment

Treatment begins on suspicion, not confirmation. Immediate actions defined by the EMHG are to stop all triggering agents; hyperventilate with minute volume two to three times normal, with 100% oxygen and high flow; declare an emergency and call for help; switch to total intravenous anaesthesia; inform the surgeon and request interruption or postponement of surgery; remove the vaporiser without wasting time changing the circuit or machine; and, if available, insert activated charcoal filters in the inspiratory and expiratory limbs. Activated charcoal filters are a main change from the 2010 version of the same guideline, alongside greater flexibility towards local symptomatic treatment routines, presentation of hyperkalaemia options only as suggestions, and updated dantrolene dosing aligned with the 2020 availability guideline and expressed in milligrams regardless of formulation [5].

Monitoring and subsequent actions include continuing usual anaesthetic monitoring, monitoring core temperature, obtaining adequate-bore venous access, inserting an arterial line and urinary catheter, considering central venous access, frequently assessing blood gases, potassium, creatine kinase, myoglobin and glucose, assessing renal and hepatic function and coagulation, looking for signs of compartment syndrome and observing the patient for at least 24 hours in intensive care or a recovery unit. If signs recur, further dantrolene doses of 2 to 2.5 mg/kg actual body weight, up to 300 mg per dose, are administered every ten minutes until resolution, with an indicative total limit of 10 mg/kg that may need to be exceeded (EMHG) [5]. For comparison, the European summary of product characteristics (SmPC) of Agilus®, which places recrudescence within the first 24 hours, indicates 2.5 mg/kg in adults and children, not exceeding 300 mg per dose and with re-examination of the diagnosis if a cumulative dose of 10 mg/kg or more is being considered, and the FDA labels indicate doses from 1 mg/kg up to a cumulative maximum of 10 mg/kg, with the regimen repeatable if signs recur [55, 82, 83].

Treatment of secondary manifestations was deliberately made open to local adaptation in the 2024 revision, arguing that familiar routines are preferable under stress. For hyperthermia, 2,000 to 3,000 mL of crystalloids chilled to 4–8 °C intravenously and surface cooling or other devices are indicated, with cooling stopped below 38.5 °C. For hyperkalaemia, listed options are insulin with dextrose, calcium chloride — or calcium gluconate if chloride is unavailable — intravenous or nebulised beta-2 agonists and dialysis. Acidosis is treated by ventilation to normocapnia, with sodium bicarbonate or another buffer if pH is below 7.2. For arrhythmias, amiodarone or magnesium is indicated and, if tachycardia persists, beta blockers. Urine output may be stimulated with crystalloids or furosemide. The case should be discussed with the local malignant hyperthermia investigation unit, and patients with suspected susceptibility should be referred to a designated laboratory for confirmation [5].

Two pharmacological safety points span all guidelines. Calcium channel blockers should not be administered with dantrolene because of potentially fatal hyperkalaemia, and should not be used to treat crisis arrhythmias [1, 10, 55]. 5-HT3 receptor antagonist antiemetics should be used cautiously, as death was reported in a child with RYR1-related multiminicore disease after a therapeutic ondansetron dose [1, 39].

Sources: [1, 5, 10, 55, 82–85].

The recommended dose is that of the guidelines: an initial dose of 2 to 2.5 mg/kg actual body weight, up to 300 mg per dose (EMHG), or 2.5 mg/kg (MHAUS and GeneReviews), repeated every 10 minutes until response, with an indicative limit of 10 mg/kg that may need to be exceeded, in which case alternative diagnoses are reconsidered [1, 5, 10]. The Japanese guideline indicates 1 to 2 mg/kg and acknowledges that international standards recommend a higher initial dose [85]. For comparison, in the European Union, including Portugal, the SmPC of Agilus® sets the initial dose at 2.5 mg/kg, with a limit of 300 mg per dose, and requires the diagnosis to be re-examined if a cumulative dose of 10 mg/kg or more is being considered; in the USA, the labels of Dantrium® Intravenous and Ryanodex® indicate a minimum of 1 mg/kg up to a cumulative maximum of 10 mg/kg [55, 82, 83]. The 2.5 mg/kg dose coincides with the European SmPC and falls within the North American labels; the lower limit of 2 mg/kg in the EMHG guideline lies below the initial dose of the European SmPC, and the doses above 10 mg/kg allowed by the guidelines exceed the cumulative maximum labelled in the USA, so that, on these points, the guideline dose falls outside the conditions of the respective label [5, 10, 55, 82, 83].

Maintenance after stabilisation is another area in which the sources differ. GeneReviews suggests intravenous bolus doses of 1 mg/kg every six hours for at least 24 hours, with no maximum dose defined in the source for this phase, with dantrolene discontinued or the interval extended to eight or twelve hours if core temperature is below 38 °C, creatine kinase is falling, muscle is not rigid, there is no myoglobinuria and metabolic stability has persisted for 24 hours [1]. MHAUS frequently asked questions state that, after 48 hours of successful intravenous treatment, dantrolene may be stopped with daily laboratory tests until creatine kinase is declining [84]. The EMHG prescribes no maintenance regimen: the crisis guideline only indicates repeating 2 to 2.5 mg/kg every ten minutes if signs recur during the 24 hours of observation, and the 2020 dantrolene guideline expressly recommends (grade 1c) that, after reversal of the episode with the loading dose, neither continuous infusion nor intermittent boluses be routinely used, because therapeutic plasma concentrations persist for approximately six hours and most patients require no more dantrolene [5, 56]. For comparison, the labels also differ from each other: the European SmPC of Agilus® provides for no maintenance regimen, only readministration on recrudescence; the FDA label of Dantrium® Intravenous indicates, after the crisis, oral dantrolene (Dantrium® capsules) 4 to 8 mg/kg/day in four divided doses for 1 to 3 days and, when the oral route is impracticable, postoperative intravenous dantrolene with the dose individualised from 1 mg/kg [55, 82]. The GeneReviews regimen of 1 mg/kg every six hours falls within this wording of the North American label and has no counterpart in the European SmPC. The divergence between guidelines should be understood: in a stabilised patient, the decision to continue or stop depends on the guideline followed by the institution and on the parameters listed, rather than on a universal regimen.

7.2. Dantrolene: formulations, mechanism and safety

Dantrolene sodium is a hydantoin molecule binding a specific region of the RYR1 channel and reducing uncontrolled intracellular calcium release, with resolution of hyperthermia, acidosis and myoglobinaemia [1]. Several formulations exist, with practically relevant preparation differences.

GeneReviews also mentions a 120 mg formulation reconstituted with 20 mL water, identified as NPJ5008, corresponding to the product that received European authorisation [1, 55].

Precautions and adverse effects are consistent across labels. High pH makes extravasation cause tissue necrosis, so administration through adequate-bore access and site monitoring are recommended; intra-arterial injection should be avoided [55, 82]. Muscle weakness is the most frequent adverse effect after administration: in analysis of 368 North American registry patients, muscle weakness was documented in 21.7%, phlebitis in 9%, gastrointestinal intolerance in 4.1% and respiratory failure in 3.8%; risk of any complication increased 29% when total dantrolene dose doubled [87]. GeneReviews, citing the same source, reports muscle weakness in 14.6%, phlebitis in 9.2% and gastrointestinal disturbances in 4.3%, with a 25% risk increase when total dose doubles the recommended initial dose of 2.5 mg/kg; the difference between the two sets of figures arises because the study presents a full and a reduced case set, so they should not be added or interchanged [1, 87]. Dantrolene may exacerbate pre-existing muscle weakness, particularly relevant in associated myopathies [1, 84]. US labels include, in the adverse reactions section, reported hepatotoxicity after intravenous products, with liver enzyme elevation hours to days later, frequently in patients with comorbidities [82]. The European summary lists jaundice, hepatitis and hepatic failure including fatal cases, with unknown frequency [55]. The boxed hepatotoxicity warning belongs to chronic oral formulation: risk of symptomatic hepatitis, including fatal cases, is much higher with 800 mg daily or more than with up to 400 mg daily, arises most frequently between the third and twelfth treatment months, is greater in women, people older than 35 years and those taking other medicines, requires transaminase monitoring and warrants discontinuation if no observable benefit occurs after 45 days [88].

7.3. Comparative regulatory status

Data verified in official databases and documents; content comparison between successive US label versions was not performed and no claim is made here that specific changes occurred in each supplement [82, 83].

The distinction between authorisation and actual access is particularly evident for this medicine. In Portugal, the public Agilus reimbursement assessment report recorded a favourable decision on 30 September 2025, for a presentation of six 120 mg vials; the identified comparators — Dantrium IV authorised in the Netherlands, Dantrolen I.V. authorised in Germany and an injectable dantrolene authorised in Canada — were, according to the same report, used in Portuguese clinical practice through exceptional use authorisation, and the new medicine was considered equivalent with an economic advantage [93]. In France, the national agency issued a communication to professionals on 1 September 2025: Agilus has been marketed since 8 April 2025 and is intended to replace Dantrium IV 20 mg, whose marketing discontinuation was scheduled for late 2025, with the last batch valid until the end of June 2027; the communication warns of medication error and overdose risk because one Agilus vial contains six times the dantrolene of a 20 mg vial, recommending separate storage and avoiding simultaneous use of both presentations in the same patient [94].

Supply shortages are a documented operational risk. In Canada, an official notification of 21 July 2025, updated on 1 April 2026, described a shortage due to manufacturing interruption with expected resolution on 1 March 2026, including extension of one batch's shelf life, and recorded restored availability in April 2026; a provincial centre issued guidance in February 2026 to retain expired stocks for emergency use. In Australia, the regulatory agency recorded a 20 mg product shortage between 3 July and 25 August 2026 due to increased demand, since resolved. No US shortage record was identified in the official database consulted, which does not exclude data in other sources [95–97].

7.4. Availability and service organisation

The quantity of dantrolene to keep in stock was addressed in a dedicated guideline. In the absence of published guidelines and high-quality evidence, the EMHG used a Delphi process with 25 experts (19 final statements, almost all grade 1c) and recommended calculating doses from actual body weight, with an initial dose limited to 300 mg; that every institution using triggers have a plan to administer the first 2 to 2.5 mg/kg bolus within 5 minutes of diagnosis and mobilise sufficient dantrolene to repeat it every 10 minutes; that dantrolene be available wherever volatile anaesthetics or routine suxamethonium are used, without this being a reason not to stock suxamethonium for airway rescue; and that regular-use locations have 36 vials of 20 mg immediately available, with 60 vials total within one hour, increasing initial stock to 48 vials if more cannot be obtained within 30 minutes and to 60 in remote locations. After stock is used, elective trigger use at that facility should be avoided until replenishment [56]. MHAUS specifies a minimum stock of 36 vials of 20 mg Dantrium or Revonto or 3 vials of 250 mg Ryanodex, available at every anaesthetising location within ten minutes of the decision to treat [84]. The quantitative basis is that some episodes required 10 mg/kg or more and delay has a measurable cost: each 30-minute delay between the first sign and first dose was associated with a 1.6-fold increase in complication probability [52, 56].

Where triggering agents are used, a treatment protocol adapted to local routines, including equipment, medication and communication pathways, should be accessible alongside dantrolene, and periodic simulations should be conducted [1, 5]. Telephone support lines exist: the US MHAUS hotline operates 24 hours a day, and equivalent lines exist elsewhere, including the United Kingdom, Germany and Brazil [1, 10].

7.5. Prevention in a susceptible person

A complete anaesthetic history addressing personal and familial episodes should be obtained for every patient undergoing anaesthesia. When susceptibility is suspected, relatives should not receive triggering agents. Generally, anyone undergoing general anaesthesia lasting more than 30 minutes should have temperature monitored with an electronic probe; liquid-crystal skin sensors are not recommended because they proved unreliable indicators of temperature change during events [1]. People with any form of myotonia should not receive suxamethonium, and people with central core disease, multiminicore disease, nemaline myopathy, congenital fibre type disproportion or dystrophinopathy should not receive triggering agents [1]. The 2026 European consensus is less restrictive in muscular dystrophies, permitting halogenated agents for inhalational induction and maintenance at the lowest doses for the shortest possible time because of perioperative rhabdomyolysis risk, otherwise preferring total intravenous anaesthesia; suxamethonium is contraindicated in both sources [73]. Susceptible individuals should have permanent identification of their condition, for example a medical alert bracelet and laminated warning card [1, 47].

European perioperative recommendations, published in 2021 after literature review to July 2020 and a two-round Delphi process (26 invited; 23 and 25 responses), explicitly address what should and should not change. The panel graded all final recommendations as strong under GRADE, with low-quality evidence (1c) — the highest possible in a consensus process — except exclusively trigger-free anaesthesia, graded 1a [11]. They apply to patients of all ages with confirmed or possible susceptibility, including untested relatives, patients with MH-associated myopathies and people with a possible uninvestigated reaction [11]. Preanaesthetic assessment should include a directed question about rhabdomyolysis, more frequent in susceptible individuals than the general population; anaesthesia should not be denied or delayed awaiting definitive diagnosis if this risks progression of the surgical disease, and, if risk cannot be excluded, the patient should be treated as susceptible. Premedication follows the same indications as for any patient, because there is no evidence that psychological stress triggers MH, and prophylactic oral or intravenous dantrolene is unnecessary and associated with unpleasant adverse effects. Only trigger-free anaesthesia should be used: regional — spinal, epidural, peripheral nerve block — or local anaesthesia is a good option and, if unsuitable, general anaesthesia without volatile agents or suxamethonium is mandatory, with prior machine preparation. With trigger-free anaesthesia, no additional monitoring is required relative to a nonpredisposed patient with the same condition; most monitoring standards recommend electrocardiography, pulse oximetry, blood pressure, core temperature and, during general anaesthesia, capnography. Recovery care is routine: no evidence supports elective intensive care admission after uncomplicated trigger-free anaesthesia, and ambient volatile concentrations in recovery are too low to trigger MH. Patients may undergo ambulatory anaesthesia according to national standards. No specific pre- or postoperative blood tests are needed, although creatine kinase, potassium and myoglobin may be reasonable with a history of elevated baseline creatine kinase, muscular symptoms or rhabdomyolysis [11, 98].

Anaesthesia workstation preparation starts from a threshold: the volatile concentration capable of inducing human MH is unknown, and the arbitrarily defined 5 ppm limit is generally accepted and should be maintained for medicolegal reasons [11]. There are three options. First, a dedicated workstation never exposed to volatile agents, rarely feasible because of cost and maintenance. Second, machine flushing, with times varying widely between models — guideline table 2 compiles times from minutes to more than two hours for common European workstations — which must be planned in advance: remove vaporisers; replace the breathing system — T-piece, circle system, reservoir bag — and soda lime with uncontaminated equipment before flushing; flush at maximum fresh gas flow of at least 10 L/min throughout the manufacturer-recommended period; without manufacturer guidance, ventilate at a tidal volume of 600 mL and rate of 15 cycles per minute in an adult; and do not place the machine on standby before use [11]. Third, licensed activated charcoal filters reduce concentrations below 5 ppm and shorten preparation: with the vaporiser off and flushing at flow above 10 L/min for 90 seconds, filters are placed in the inspiratory and expiratory limbs and the circuit and soda lime replaced; flow may then decrease to 3 L/min and, with the circuit and soda lime replaced, usual flows with a minimum of 1 L/min may be used; filters remain throughout anaesthesia, and the manufacturer specifies replacement every 12 hours [11]. Step order differs slightly between the recommendation text and the Delphi statement, which specified replacing the circuit before inserting filters, and the group's 2018 website recommendation described replacement before the 90-second flush [11, 99]. Because of conflicts of interest related to availability and cost, the guideline does not require keeping filters in stock but suggests using them when available [11]. The 2018 recommendation graded the first two recommendations as strong with evidence level 2- and filters as a weak good-practice recommendation, differing from the 2021 article, in which all these recommendations are strong [11, 99].

Regarding agents and circumstances to avoid, beyond potent volatile agents and suxamethonium, the EMHG position on inhaled analgesic-dose methoxyflurane is that it should be avoided in susceptible individuals because of episode-triggering risk, with alternative analgesia offered; passive exposure of a susceptible person to air exhaled from a correctly assembled device with an activated charcoal filter poses no risk because measured concentrations are well below the 5 ppm threshold considered the lower risk limit [6]. Regarding heat and exercise, susceptible individuals are advised to avoid extremes of heat but not to restrict physical activity or lifestyle unless they have had overt rhabdomyolysis or heat stroke; strenuous activities at high ambient temperatures should be avoided or undertaken cautiously [1]. In cardiopulmonary bypass surgery, aggressive rewarming should be avoided, as it has been associated with clinical signs [1]. Regarding occupational exposure, international consensus holds that, when hazardous-substance control standards are met, susceptible individuals are not at risk of MH through occupational exposure in theatres, recovery or intensive care, because the necessary dose is considerably above permitted limits; before starting work, three baseline creatine kinase determinations over one week, with physical activity comparable to that expected, are recommended as reference values if later concerns arise [100].

7.6. Pregnancy, delivery and special populations

European pregnancy recommendations, revised in May 2026, distinguish two situations: the mother is susceptible, in which case the fetus may also be at risk, or only the fetus is at risk because the father is susceptible. In both, recommendations with very high consensus are that the anaesthetic plan be prepared antenatally, that the anaesthesia team be informed as soon as the pregnant woman is admitted to the delivery suite or scheduled for nonobstetric surgery, and that the team ensure the capacity to provide trigger-free general anaesthesia, preparing the workstation according to the group's recommendations. In planned vaginal delivery, early epidural analgesia should be considered, allowing rapid conversion to epidural anaesthesia for emergency caesarean delivery. Neuraxial anaesthesia is preferred for caesarean delivery in all situations of known or possible risk, except when general anaesthesia is required for obstetric indications or there are contraindications to blockade. If general anaesthesia is required, it should be directly supervised by an experienced anaesthetist; suxamethonium and volatile agents are contraindicated, noting that nitrous oxide is not a trigger and may be used. Propofol, barbiturates, ketamine and etomidate may be used for induction and maintenance, and any opioid as a supplement. Relaxation for intubation should be obtained with nondepolarising blockers, preferably rocuronium at a dose of 1 mg/kg ideal body weight, with sugammadex 16 mg/kg readily available. The anaesthetist is advised to use the combination of nontriggering drugs with which they are most familiar [101]. For comparison, in the FDA label the rocuronium dose for rapid-sequence intubation is 0.6 to 1.2 mg/kg, calculated on actual body weight in the obese patient, and sugammadex 16 mg/kg is indicated for immediate reversal approximately 3 minutes after 1.2 mg/kg of rocuronium, in adults only, because immediate reversal has not been studied in paediatric patients (FDA label and European SmPC of Bridion®); the calculation on ideal body weight recommended by the EMHG differs from the actual body weight used in the FDA label [102–104].

Two points in this guideline warrant attention because of their nature. First, prenatal genetic testing is not recommended: even without the familial variant, the fetus should be considered at increased risk according to the group's own diagnostic guidelines [101]. This contrasts with GeneReviews, which states that, once a causal variant is identified in an affected relative, prenatal diagnosis and preimplantation genetic testing are possible [1]. The difference concerns recommendation rather than facts: the EMHG considers that the result does not change anaesthetic management, whereas GeneReviews describes technical test availability. Second, there was no consensus on suxamethonium use when only the fetus is at risk; arguments against include uncertainty about placental transfer amounts, availability of safe alternatives and unnecessary complication of recommendations [101].

GeneReviews adds that dantrolene should not be given in preparation for surgery or delivery, monitoring should follow American Society of Anesthesiologists standards plus core temperature, and fetal monitoring follows usual standards; when the father is susceptible and the mother is not, it recommends regional or trigger-free general anaesthesia, because a volatile agent crossing the placenta, administered to the unaffected mother, may trigger a potentially severe or fatal reaction in the affected fetus [1]. The North American review reiterates the same reasoning, highlighting that paternal-line family history may inadvertently be overlooked and epidural analgesia during labour creates no fetal risk [14].

In paediatrics, the CPIC guideline notes less experience than in adults, with unpublished observations suggesting possibly greater risk when the anaesthetic is administered in childhood, and states that identification of a causal variant in a parent should prompt full assessment of all at-risk relatives, including children, with the qualification that interpreting a negative result in a relative is complex and controversial and should involve a specialist in the condition's genetics. Triggering agents are relatively contraindicated in all susceptible patients regardless of age [12].

7.7. Management of associated myopathies

In RYR1- and STAC3-associated myopathies, no therapy stops or reverses manifestations; treatment is symptomatic and organised by a multidisciplinary team. For STAC3 myopathy, GeneReviews recommends occupational therapy and physiotherapy for range of motion and mobility, adaptive devices, intervention for feeding difficulties, speech therapy, scoliosis treatment and respiratory failure support. Decisions about timing and type of palatal surgery should be made by a multidisciplinary craniofacial team given comorbidities, and ptosis intervention may be performed by ophthalmology within that team. Surveillance covers growth, musculoskeletal complications such as scoliosis and contractures, speech development, swallowing function, respiratory function and educational needs. Specific measures include physiotherapy for joint range, stretching, night splints or serial casting, avoiding prolonged postoperative immobilisation, orthopaedic treatment of talipes equinovarus with serial casts, splints and surgery when necessary, surgical ptosis correction through levator resection or frontalis suspension, and nutritional support with calorie-dense foods or formulas and enteral feeding when needed [4].

Recommended initial assessment includes height, weight and head circumference measurement, neurology referral, neuromuscular clinic assessment including physical medicine and rehabilitation, orthopaedic assessment, ophthalmological assessment with extraocular movements, acuity and visual fields, feeding assessment by speech therapy, occupational therapy or nutrition, with videofluoroscopic swallowing study when indicated, craniofacial team assessment of palatal abnormalities, respiratory assessment with polysomnography for central or obstructive apnoea and hypoxia, spirometry with maximal inspiratory and expiratory pressures and peak cough flow, genetics consultation and review of surgical history for evidence of an MH episode [4].

The European consensus on anaesthesia in neuromuscular disorders adds specific recommendations for congenital myopathies: assess the need for fibreoptic intubation with craniofacial abnormalities, noting that intubation may be difficult in forms with spinal rigidity and reduced neck movement, especially SELENON- and NEB-associated forms; pay particular attention to respiratory involvement in forms caused by MTM1, NEB, ACTA1, TTN and RYR1 variants, especially recessive variants, because respiratory impairment may be disproportionate to girdle weakness; monitor nutrition, as reduced muscle mass may cause postoperative hypoglycaemia up to several days after surgery; and consider cardiac involvement in TTN myopathies and rarer MYH7 forms [15]. The same consensus states that volatile agents are strictly contraindicated in neuromuscular patients with RYR1 variants because of possible susceptibility unless the variant has been classified as benign for MH according to expert panel recommendations, and that patients with CACNA1S and/or STAC3 variants should be referred to an MH investigation centre before exposure [15]. With RYR1 and/or CACNA1S variants, referral to an MH centre for guidance is recommended; if the centre cannot be contacted before surgery, for example in an emergency, volatile agents and/or suxamethonium are contraindicated [15]. In STAC3 myopathy, GeneReviews lists anaesthetic agents with high malignant hyperthermia-triggering risk as circumstances to avoid, emphasising that patients should discuss the diagnosis with the anaesthetist before any procedure [4].

The 2026 EMHG consensus on perioperative management of patients with primary inherited muscle disease — developed between February 2019 and February 2024 by a nine-member writing group and a panel of 27 experts in neuromuscular disease or paediatric anaesthesia and EMHG directors, with three Delphi rounds (response rates 95%, 74% and 74%) and GRADE grading (1c for recommendations, 2c for suggestions, plus «major concerns» and «uncertainty») — applies to myopathies with pathology distal to the neuromuscular junction, classified by ICD-11 [73]. General recommendations include establishing the most likely neuromuscular diagnosis before moderate or major elective surgery in patients with moderate to severe symptoms; comprehensive preanaesthetic assessment; targeted laboratory tests according to myopathy type and severity; electrocardiogram and echocardiogram when the myopathy is associated with cardiac involvement or cardiac dysfunction is suspected; respiratory function tests in the presence of signs of reduced capacity, with high pulmonary complication risk if forced vital capacity is below 60% of normal; active warming before induction in cold-exacerbated myopathies; avoiding benzodiazepine premedication if there is weakness; preferring regional anaesthesia; contraindicating suxamethonium; rocuronium instead of suxamethonium for rapid-sequence induction, with sugammadex available; remifentanil or alfentanil bolus as an alternative to blockade for intubation; titration of nondepolarising blockers with mandatory quantitative train-of-four ratio monitoring, advising dose reduction to below 50% of usual (for example, rocuronium 0.3 mg/kg rather than 0.6 mg/kg) and requiring a ratio above 0.9 before extubation; preference for vecuronium or rocuronium, reversible with sugammadex at a dose of 2 to 8 mg/kg; multimodal analgesia; patient-controlled analgesia only with continuous oximetry; and intensive care available and planned when the myopathy is functionally significant [73]. For comparison, in the sugammadex labels (Bridion®, FDA and European SmPC) the doses are 2 mg/kg after reappearance of T2, 4 mg/kg with 1 to 2 post-tetanic counts and 16 mg/kg for immediate reversal, on actual body weight; the 8 mg/kg dose included in the consensus range corresponds to no labelled posology; the usual intubation dose of 0.6 mg/kg of rocuronium, from which the consensus starts, is that of the label, and the reduction to less than half in myopathies has no counterpart in the label [73, 102–104].

In its text on RYR1-related myopathies, the consensus considers increased MH risk a real concern when congenital myopathy has an RYR1 aetiology, extends this to RYR1-associated exertional or recurrent rhabdomyolysis and acknowledges that some loss-of-function ryanodinopathies have a lower probability of association with increased risk; for STAC3 disease it describes a strong association with increased MH risk under anaesthesia; and it states there is no evidence that halogenated agents cause MH in CASQ1, ATP2A1, KCNA1 or TRPV1 myopathies [73]. Compared with the 2022 ENMC consensus, one difference is the explicit exception for a patient with their own negative IVCT; the ENMC allowed an exception for a variant classified as benign for MH by the expert panel [15, 73].

A practical note in the Brazilian material illustrates convergence of this article's two themes: in central core disease, surgery may be needed for congenital hip dislocation, with the high malignant hyperthermia risk during induction using halothane and suxamethonium considered [63].

7.8. Investigational therapies and developments over the past twelve months

No disease-modifying therapy is authorised for RYR1-related disorders. Salbutamol, pyridostigmine and N-acetylcysteine have been investigated without demonstrated efficacy [1].

Interpretation requires specific cautions. The phase 1 channel stabiliser trial's primary objective was safety, with only seven participants and no comparator: reported fatigue and strength improvements are exploratory endpoints in an open-label study and do not demonstrate efficacy; the company announcement, which called the study «phase 1b» and described «significant» fatigue relief in the high-dose group, is a sponsor statement rather than a peer-reviewed result [106, 109]. The phase 2 trial is recruiting and has no results. Comparing the six-minute walk endpoint of the negative N-acetylcysteine trial with the sit-to-stand test of the ongoing trial would be an invalid indirect comparison of different instruments in different populations. The N-acetylcysteine trial is relevant precisely because it was negative: it documented stable disease over six months, confirmed elevated oxidative stress and reduced physical endurance relative to the general population, and excluded treatment effects on the selected biomarker [105].

Gene and molecular therapies for RYR1 remain preclinical according to the sources consulted, including gene-editing and allele-specific ribonucleic acid interference approaches; no human gene therapy or antisense oligonucleotide trial for RYR1 was identified. A Cochrane systematic review entitled «Treatments for RYR1-related disorders» is published only as a protocol without results [110]. Absence of these findings refers to the sources and databases consulted and does not prove absence of programmes.

For concentrated dantrolene in exertional heat stroke, the US authority issued a complete response letter in July 2017; according to an August 2020 sponsor announcement reported by a secondary source, a further complete response letter and decision to stop pursuing this indication followed; no subsequent activity was identified. The two registered studies in this indication were very small: in one, five of seventeen active-group participants versus two of seventeen comparators recovered a coma scale score of 13 or higher, without statistical significance (p = 0.396); in the other, with seventeen participants, four of nine versus two of eight at ninety minutes, without a deposited statistical analysis [111–113]. These figures illustrate why dantrolene efficacy in the anaesthetic crisis cannot be extrapolated to exertional heat stroke.

In the twelve months preceding this article's date, identified developments are mainly guideline and regulatory changes: the 2025 EMHG diagnostic guideline revision, published in January 2026, introducing MH genotype designation, the first consensus definition of a clinical event, a simplified IVCT protocol and new diagnostic pathways, with an August 2026 corrigendum restricted to group membership; the same group's consensus on perioperative management of primary inherited muscle disease, published online in July 2026 and in the September issue; the proposed North American approach to genetic testing, published in April 2026 with an affirmation of value from the American Society of Anesthesiologists and endorsement by the Canadian society; the 2025 Japanese guideline, published in 2026; the Portuguese reimbursement decision for 120 mg dantrolene in September 2025; the September 2025 French communication on presentation replacement; and Swedish and French national cohort data published in 2026 [9, 14, 67, 68, 73, 85, 93, 94]. No new US intravenous dantrolene authorisation was identified in the period, nor a new pharmacogenetic guideline publication, whose record indicates a June 2026 content update without corresponding publication [12, 82].

8. Reproductive Options and Family Counselling

Nonsyndromic susceptibility is autosomal dominant. Most diagnosed individuals have an equally susceptible parent, although that parent may never have had an episode. Each child of a susceptible person has a 50% probability of susceptibility [1, 47]. De novo variants have been detected, but the proportion of cases explained this way is unknown. If neither parent is known to be susceptible, assessment is recommended to inform recurrence risk and their own risk, through a multigene panel if the proband's variant is known and contracture testing at an accredited centre [1].

When the proband's variant is not detected in either parent, with biological maternity and paternity confirmed, two possibilities should be considered: a de novo variant in the proband or inheritance from a parent with gonadal or combined somatic and gonadal mosaicism, noting that parental leucocyte deoxyribonucleic acid testing may not detect all somatic mosaicism and does not detect variants present only in germ cells [1]. The Icelandic report provides a documented example: in a ten-year-old child with a suspected episode, a heterozygous RYR1 missense variant was identified, present in four individuals across three family generations and absent from 62,240 Icelandic genomes and 30,000 genomes of other origins; the paternal grandmother had an allele ratio of 0.21 on genome sequencing and 0.20 on Sanger sequencing, a deviation consistent with mosaicism, whereas the three carrier descendants had balanced ratios, indicating a de novo mutation occurring in the grandmother and subsequently transmitted [38].

Sibling risk depends on parental status. If one parent is susceptible or a known carrier, risk is 50%. If the proband has a causal variant undetectable in either parent's leucocyte deoxyribonucleic acid, sibling risk of inheriting the variant is estimated at 1% because of possible parental gonadal mosaicism [1, 114]. Family history may appear negative because of reduced penetrance or absence of a triggering event in heterozygous relatives: an apparently negative family history cannot be considered confirmed without appropriate parental assessment [1].

Assessment of at-risk relatives aims to identify who benefits from avoiding triggering agents. If the familial causal variant is known, molecular testing establishes increased risk in heterozygotes and should use a multigene panel; testing only the familial variant is considered inadequate and discouraged. If a relative tested with a panel including all three genes has neither the familial variant nor any other pathogenic or likely pathogenic variant in these genes, their risk is probably equal to or below the general population. If the familial variant is unknown, or the relative was negative only on targeted testing without a panel, contracture testing at an accredited centre can assess susceptibility; without this difficult-to-access test, close relatives should be treated as susceptible [1]. The EMHG formulates the principle differently. In its 2025 review, familial-variant cascade screening is a pathway benefiting from molecular diagnosis, but in families with a clinical reaction absence of a pathogenic or likely pathogenic variant in a relative does not exclude risk: only negative IVCT permits MHN classification, and those classified as without risk do not transmit risk to offspring; in families where the variant was incidental, without clinical history, relatives may be diagnosed by genetic testing alone [9]. The 2015 version indicated contracture–genetics discordance in approximately 5% of families and advised considering IVCT if a relative sought maximum assurance [65].

For family planning, the optimal time to determine genetic risk and discuss prenatal and preimplantation testing availability is before pregnancy, and offering genetic counselling, including offspring risks and reproductive options, to affected or at-risk young adults is appropriate [1]. Once a causal variant is identified in an affected relative, GeneReviews considers prenatal and preimplantation genetic testing possible, adding that perspectives may differ between professionals and within families regarding use, and most healthcare professionals would consider this a personal decision [1]. In its 2026 pregnancy guideline, the EMHG does not recommend prenatal genetic testing, arguing that even without the familial variant the fetus should be considered at increased risk [101]. This divergence should be communicated neutrally: informed decision-making depends on the family understanding that a negative prenatal result does not alter recommended anaesthetic management under the European position.

Deoxyribonucleic acid banking should also be considered in probands without a confirmed molecular diagnosis, as testing methods and knowledge of genes and mechanisms will evolve [1]. For recessively inherited STAC3 myopathy, each sibling of an affected person has, at conception, a 25% probability of being affected, 50% of being an asymptomatic carrier and 25% of being neither affected nor a carrier; unless the reproductive partner of an affected person also has the disorder or is a carrier, offspring will be obligate carriers. Once variants are identified in an affected relative, carrier testing in at-risk relatives, prenatal testing in an increased-risk pregnancy and preimplantation testing are possible [4].

A specific counselling aspect is information about risks outside anaesthesia. MH risk predominantly concerns general anaesthesia with triggering agents, but some susceptible people also appear at risk of heat stroke or exercise-induced rhabdomyolysis, and episodes without anaesthetic exposure have been described [1]. The North American review recommends that susceptible people taking part in sports, working in occupations involving heat stress or extreme physical exertion, or planning risky activities inform supervisors, employers, coaches and companions, providing education about crisis recognition and assistance, and reiterates the importance of medical identification [14].

The EMHG devoted a recommendation to life insurance implications, listing unresolved questions: whether clinically confirmed proband susceptibility and predictive contracture or genetic data should be disclosed to the insurer, given that underwriting requires complete and accurate risk description and insurers have a legitimate assessment interest, conflicting with rights to privacy, self-determination and not knowing enshrined in the Convention on Human Rights and Biomedicine; whether susceptibility can lead to increased premiums, limited insurer liability, contract termination or exclusions; whether professionals have or may have a duty to warn other relatives of risk; and whether they may be requested to disclose medical record information to insurers with patient consent [115]. The document poses these questions without resolving them, reflecting legal variation between countries, and should be presented accordingly during consultation.

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency: three distinct measures

Epidemiology requires separating three noninterchangeable quantities: reaction frequency per anaesthetic administered, prevalence of recorded diagnoses in hospital populations and carrier frequency in genomic databases. The difference between the third and the first two is precisely incomplete penetrance associated with the need for exposure.

The last study is particularly instructive because it quantifies dependence of the estimate on curation criteria: the same population produces frequencies differing by more than a factor of fifteen depending on whether only expert-validated variants or all ever-reported variants are accepted [121]. This yields a reading rule: any susceptibility prevalence figure should state the variant source used.

Penetrance was quantified in a multicentre case–control study using 125 pedigrees from four European registries and one Canadian registry, between 1994 and 2017, including reaction-surviving probands and relatives with at least one triggering-agent exposure, all carrying a diagnostic RYR1 variant. Overall penetrance of nine variants was 40.6% (93 in 229), without statistical differences between variants. Reaction probability with exposure was 0.25 among all carriers and 0.76 among probands. Penetrance was significantly higher in men (50%, 62 in 124) than women (29.7%, 30 in 101; p = 0.002), with an odds ratio of 2.37 (95% confidence interval: 1.36 to 4.12) despite similar exposure levels; median proband age was 12 years [7]. Population genomic data, showing variant prevalence one to two orders of magnitude higher than reaction rates, suggest penetrance below 5% when the denominator is the population rather than clinically ascertained families [1, 71].

9.2. Data by country and population

In the United States, beyond the cited hospital prevalences, analysis of the national inpatient sample between 2000 and 2005 documented an increase in annual cases from 372 to 521, median age 39 years, 17.8% children and hospital mortality ranging from 6.5% in 2005 to 16.9% in 2001, with lower mortality in children (0.7%) than adults (14.1%); adjusted mortality was associated with age, female sex, comorbidity burden, admission source and geographical region [117]. The North American registry provided the detailed clinical description already cited [52] and data on dantrolene complications [87] and recrudescence [54].

In the United Kingdom, the national referral service cohort confirmed susceptibility in 795 independent families since 1971, with genetic analysis since 1991, and estimated that 14 to 23% of families have a cause outside the three known genes, in a predominantly white European population [46]. In Sweden, the national registry comprises 2,852 people from 544 families investigated since 1980, with susceptibility confirmed in 1,555; among 288 index cases with a reaction history and confirmed susceptibility, 58% were male and 57% younger than 18 years; overall case fatality after reaction was 5.2%, with no deaths reported since 2001; of 163 genetically investigated families, 61 had a diagnostic variant and 23 a variant of uncertain significance, corresponding to fewer than 40% of investigated families and approximately 20% of all Swedish families with an established genetic diagnosis [68]. In France, a referral-centre cohort between 1968 and 2020 assessed 1,258 people, of whom 182 had a suspected crisis and 93 were fully investigated, with 49 susceptible and 44 negative; appropriate dantrolene treatment was administered in 64% of cases after 2000 [67]. In Iceland, actionable variant carrier frequency was 1 in 1,450 in a population of approximately 360,000 [38].

Among populations with founder variants, the best characterised is North Carolina's Lumbee tribe, state-recognised and with approximately 60,000 enrolled members, whose ancestry combines indigenous Cheraw, English and African American components. An estimated 1 in 5,000 members has STAC3 myopathy, and the conservative Lumbee prevalence estimate published with the fourteen-patient series was approximately 2 per 10,000, with unknown birth incidence [4, 49]. The founder variant is the same one identified in families of highly diverse ancestries: among eighteen patients from twelve families in an international series, seventeen from eleven families were homozygous for it, including five families of African ancestry, three Middle Eastern, one Afro-Caribbean, one from the Comoros and one South American [4, 40]. The myopathy was identified in Qatari and Puerto Rican families initially assessed for suspected other syndromes [122].

In Brazil, two contributions are relevant. A series of nine Brazilian families with central core disease identified two with two RYR1 variants, clinically asymptomatic heterozygous parents and mildly affected patients, suggesting that recessive inheritance may be more frequent than previously described, with implications for counselling and malignant hyperthermia prevention in affected families [123]. Two paediatric STAC3 myopathy cases were described in Ceará in children without Lumbee ancestry, both homozygous for the founder variant, leading the authors to propose considering gene screening with a compatible phenotype regardless of ancestry [124]. The Brazilian unit follows the EMHG protocol, and the country has diagnostic centres and a telephone support line [1, 17]. The Universidade Federal de São Paulo malignant hyperthermia centre is represented in the signatory group of the 2025 European diagnostic guideline, through a correction published in 2026, and in authorship of the 2026 European consensus on inherited myopathies [9, 73].

In Portugal, the sources consulted provided regulatory information — the 2025 reimbursement decision for 120 mg dantrolene and use of previous products through exceptional use authorisation — but no national epidemiological incidence or susceptibility prevalence data [93]. This absence concerns sources actually consulted, without targeted geographical searches, and does not prove absence of published Portuguese studies.

Two diversity observations warrant recording. First, the study of African American men with exertional rhabdomyolysis identified a previously susceptibility-associated variant as a predominant polymorphism in people of African ancestry, emphasising the need for adequate population data when interpreting variants outside the most studied populations [37]. Second, estimated carrier frequency critically depends on the databases used, which continue to underrepresent several ancestries, so the presented figures derive mainly from European and North American populations [8, 121].

10. Illustrative Clinical Case

10.1. Episode in a six-week-old infant with genetic confirmation

A six-week-old male infant weighing 3.9 kg underwent microlaryngoscopy and laparoscopic diaphragmatic hernia repair. He had been transferred from another institution to neonatal intensive care because he could not be weaned from continuous positive airway pressure; besides retrognathia, he had a ventricular septal defect and suspected central congenital diaphragmatic hernia. Anaesthesia was induced with intravenous ketamine and mask sevoflurane; otorhinolaryngology found redundant arytenoid tissue and performed supraglottoplasty, followed by intubation and sevoflurane maintenance. During repositioning for laparoscopy, the infant developed progressive hypercapnia, with expired carbon dioxide rising from 50 to a peak of 75 mmHg despite vigorous manual ventilation, tachycardia from 170 to 209 beats per minute and rectal temperature rising from 36.8 to 38 °C. Generalised muscle rigidity developed, with arms flexed over the chest and legs over the pelvis, hindering positioning and persisting despite 5 mg intravenous rocuronium. The team stopped inhalational anaesthetics and requested the malignant hyperthermia trolley and assistance [125].

Over the following fifteen minutes, muscle tone normalised, expired carbon dioxide and heart rate returned to baseline and femoral arterial blood gas analysis showed pH 7.34, carbon dioxide partial pressure 45 mmHg, bicarbonate 24.3 mmol/L, base excess −2, lactate 1.5 and potassium 4.8 mmol/L. Given these results and the favourable trend, the team decided not to administer dantrolene. Surgery was not begun and the infant returned intubated to neonatal intensive care. Serum creatine kinase was elevated at 1,056 units per litre on arrival and peaked at 4,914 the next morning, without recurrence. Hernia repair was subsequently performed under total intravenous anaesthesia, uneventfully, with fentanyl, ketamine and midazolam. Exome sequencing identified two RYR1 variants: NM_000540.3:c.6487C>T p.(Arg2163Cys), considered diagnostic for malignant hyperthermia and shared with the father, and NM_000540.3:c.5011G>A p.(Ala1671Thr), of uncertain significance and shared with the mother; testing of the two older siblings was underway and the family received counselling about the need for nontriggering anaesthetics [125]. The image of intraoperative vital signs is available in figure 1 of the original article, which is open access [125].

The case is instructive on several levels. The authors emphasise that, in neonates and infants with respiratory comorbidities, baseline tachycardia and hypercapnia make signs less alarming than at other ages, and unexpected muscle rigidity, especially without response to a nondepolarising blocker, is particularly informative because the process involves muscle rather than the neuromuscular junction. The North American registry analysis they cite shows that children aged 0 to 24 months have lower peak creatine kinase than older children and a lower mean maximum temperature (38.4 °C versus 40.2 °C in adolescents), helping explain the attenuated presentation [125, 126]. Case description must nevertheless be separated from recommendation: the authors themselves state that, although the episode resolved without dantrolene, the drug should be administered at the full initial 2.5 mg/kg dose whenever malignant hyperthermia is suspected, with additional doses until signs regress, and there is no evidence of increased dantrolene adverse effects in younger patients [125]. Nonadministration in this case therefore does not constitute recommended management.

The case also illustrates the growing role of genetic testing: most centres do not perform contracture testing below age five because of the muscle quantity required, whereas sequencing can be performed at any age and, when it identifies a diagnostic variant, establishes susceptibility and avoids biopsy, while allowing family assessment — identifying the father as a carrier in this case [1, 125].

10.2. Two Brazilian cases of STAC3-related myopathy

Two unrelated Brazilian boys, children of nonconsanguineous parents without Native American ancestry, were assessed at a neurogenetics centre. The first, aged 8 at description, had motor and speech delay from 4 months, generalised weakness and feeding difficulties from age 3; he achieved head control at 12 months, sat independently at 24 and walked independently at 30 months. He had a sister who died at 4 months from respiratory complications after being born hypotonic, two healthy sisters and a cousin who died at age 10 with generalised weakness. Examination showed myopathic facies, facial hypomimia, bilateral ptosis, global atrophy and hypotonia, areflexia, Gowers' sign, ligamentous laxity and short stature, with normal speech, cognition and school performance. Electromyography showed a myopathic pattern; creatine kinase was normal; respiratory function tests showed moderate restrictive disease; cerebral MRI was normal; he had bilateral hearing loss and obstructive sleep apnoea, with kyphoscoliosis measuring 31 degrees by Cobb angle. Exome sequencing identified homozygous pathogenic STAC3 variant c.851G>C, p.(Trp284Ser). The second, aged 3, was born hypotonic, required resuscitation and prolonged mechanical ventilation, had recurrent respiratory infections and required a nasogastric tube for dysphagia; he achieved head control at 6 months, sat with support at 10 and walked independently at 25 months. He had global hypotonia, areflexia, bilateral facial paresis, a broad-based myopathic gait, high-arched palate, ptosis, lordosis and bilateral congenital talipes equinovarus. A next-generation sequencing panel identified the same homozygous variant. Both received physiotherapy and pulmonary rehabilitation, and the second also speech therapy for dysphagia [124]. Clinical features are documented in figures 1 and 2 of the open-access article [124].

Neither had a malignant hyperthermia episode, even after surgery for talipes equinovarus correction; both investigations covered RYR1 and CACNA1S, without pathogenic variants in these genes. The authors place this finding within the discussion of STAC3-associated susceptibility, recalling that absence of an episode does not exclude risk, and emphasise that early diagnostic recognition serves precisely to avoid procedures using triggering anaesthetics [124]. The second patient was initially referred with suspected Moebius syndrome, a diagnosis corrected only after molecular testing, illustrating the phenotypic overlap described in the differential and the usefulness of reverse phenotyping [4, 124]. The authors also note that, although consanguinity is frequent in this condition and unconfirmed in these families, the first patient's parents came from a small inland Ceará town where consanguinity is relatively common, and both families had lived in the state for at least three generations [124].

11. Prognosis and Long-Term Follow-Up

Episode prognosis depends almost entirely on early recognition and speed of treatment. Without appropriate dantrolene treatment, mortality may exceed 80%; with early diagnosis and treatment, morbidity and mortality are much lower than when the syndrome was first recognised, although mortality may reach 11% [1, 117]. The British reference source describes case fatality falling from 70% to 5% after dantrolene introduction [47]. Recent national data document sustained improvement: in Sweden, overall case fatality after reaction was 5.2%, with no deaths since 2001 [68]. This trend does not justify complacency, because improvement depends on organisational conditions — temperature monitoring, immediate dantrolene availability, team training — not guaranteed everywhere [52, 56].

During recovery, swollen muscle and creatine kinase normalise within ten to fifteen days in survivors, while symptom resolution may take longer [1]. Intensive care observation for at least 24 hours, extended to 24 to 36 hours according to GeneReviews, is justified by recrudescence probability of 20 to 25% in registry series [1, 5, 54]. Blood gases, electrolytes, creatine kinase, blood and urine myoglobin and coagulation profile should be monitored every six to twelve hours, continuing creatine kinase surveillance until normalisation; the earliest rhabdomyolysis sign is myoglobinuria or myoglobinaemia, as creatine kinase may not rise for several hours. Patients with extreme hyperthermia are at risk of disseminated intravascular coagulation and should have coagulation assessment. Myoglobinuria requires neurology referral for further investigation [1].

After the episode, follow-up shifts to three areas. First, diagnostic confirmation: refer the patient to a diagnostic centre for biopsy and contracture testing after discussion with specialist consultants, and register the case — in the United States through the adverse metabolic reaction to anaesthesia form for inclusion in the North American registry [1]. Second, extension to the family, described in section 8. Third, surveillance of muscular manifestations outside anaesthesia, recognised as a distinct phenotype expressed throughout adulthood and including cramps, stiffness, myalgia, rhabdomyolysis and weakness, with documented impact on quality of life, sleep and rest, walking, activities of daily living and recreation [32, 62]. This dimension justifies early counselling after diagnosis and multidisciplinary management, and should not be treated as an incidental complaint [32].

For those working with volatile anaesthetics, three baseline creatine kinase determinations over one week before starting work are recommended for future comparison if concerns about chronic exposure arise; international consensus is that, with exposure control standards met, occupational exposure poses no malignant hyperthermia-triggering risk [100].

In associated myopathies, prognosis depends on subtype. In central core and multiminicore disease, the Brazilian source describes normal life expectancy with nonprogressive weakness, although some patients are severely affected and require a wheelchair, and with malignant hyperthermia risk from halogenated agents and suxamethonium-derived relaxants; in severe neonatal nemaline myopathy, prognosis is poor, with death from respiratory failure generally in the first year, and X-linked centronuclear myopathy forms are common and severe [63]. Identifying the causal gene helps predict prognosis and plan monitoring [63]. In STAC3 myopathy, recommended surveillance covers growth, scoliosis and contractures, speech development, swallowing, respiratory function and educational needs [4]. In RYR1-, SELENON- and ACTA1-associated forms, cardiac involvement is rare, unlike titinopathies, in which cardiac follow-up is recommended at diagnosis and annually thereafter with electrocardiogram and echocardiogram [64].

Available networks and resources structure this follow-up. The relevant European Reference Network is ERN EURO-NMD, dedicated to rare neuromuscular diseases [16]. The European Malignant Hyperthermia Group maintains the diagnostic protocol, diagnostic variant list, unit map — in Europe, South Africa, Brazil, Australia and New Zealand — and a suspected-event registry [17, 35]. In the United States, the Malignant Hyperthermia Association of the United States provides a 24-hour emergency hotline, educational materials and centre list, and the North American registry collects cases [1, 10]. There is also an Australia and New Zealand group and patient organisations dedicated to RYR1-related disorders [1, 127]. Brazil has a unit following the European protocol and a telephone support service [1, 17].

12. Summary and Final Considerations

Malignant hyperthermia susceptibility is a skeletal muscle pharmacogenetic condition in which exposure to potent volatile anaesthetics or suxamethonium triggers uncontrolled calcium release through ryanodine receptor type 1, with hypermetabolism, contracture, acidosis, rhabdomyolysis and risk of death. The three known genes — RYR1, CACNA1S and STAC3 — control the same excitation–contraction coupling step and explain approximately 70 to 75% of cases, leaving a substantial fraction without an identified molecular cause [1, 14, 46].

Three asymmetries organise clinical practice. First, between genotype and phenotype: population carrier frequency is one to two orders of magnitude above reaction frequency, and penetrance measured in clinically ascertained families is approximately 40%, with a significant sex difference; neither figure transfers to the other context [1, 7, 71]. Second, between test sensitivities: contracture testing retains high sensitivity but is practically inaccessible in several regions, whereas genetic testing is accessible but has sensitivity up to approximately 70%, making a negative result inconclusive and requiring integration with personal and family history [1, 14, 69]. Third, between isolated susceptibility and associated myopathies: a myopathy-causing variant may not confer susceptibility, and anaesthetic risk assessment of a patient with RYR1-related myopathy cannot be resolved by extrapolating from the diagnostic variant list [1, 15].

In treatment, the sequence is known and delay is the main modifiable determinant of outcome: discontinue triggers, hyperventilate with pure oxygen, administer dantrolene early and repeat it, cool, treat hyperkalaemia, acidosis and arrhythmias without calcium channel blockers, ensure urine output and observe for at least 24 hours because of possible recrudescence [1, 5, 10]. The initial dose recommended by the European and North American society guidelines is 2 to 2.5 mg/kg, and the Japanese guideline indicates 1 to 2 mg/kg; for comparison, the North American labels indicate a minimum of 1 mg/kg up to a cumulative maximum of 10 mg/kg and the European SmPC 2.5 mg/kg in adults and children, up to 300 mg per dose; the team should be aware of these differences and follow the standard adopted in its institution [5, 55, 82, 85]. Drug availability in defined quantities and time, anaesthesia workstation preparation and periodic training are components of the intervention rather than accessories [56, 99].

For prevention, management is simple and effective: trigger-free anaesthesia, without routine pharmacological prophylaxis, with core temperature monitoring, routine postoperative care and the possibility of ambulatory surgery. Permanent patient identification and testing relatives complete the strategy [1, 11, 98].

Unresolved questions are identifiable. Genetic cause remains unknown in a significant proportion of families, and uncertain variants remain numerous, with only a minority supported by functional data despite recent assay calibration [8, 43]. The relationship between susceptibility, exertional heat illness and rhabdomyolysis remains under investigation, with recognised genetic heterogeneity [1, 61]. Muscular manifestations outside anaesthesia have only recently been systematised as a distinct phenotype, and patient-reported outcome instruments are now being characterised for trials [32, 62]. The only channel-targeted therapy in clinical development is in phase 2 without results, following a small open-label phase 1 trial [106, 107]. Finally, introduction of an MH genotype designation and consensus clinical event definition in the 2025 European diagnostic revision changes the vocabulary used to classify these patients, and divergence between that revision and the North American proposal in uncertain variant interpretation mainly reflects unequal IVCT access [9, 14].

13. Bibliographical References

1. Riazi S, Biesecker LG, Rosenberg H, Dirksen RT. Nonsyndromic Malignant Hyperthermia Susceptibility. In: GeneReviews® [Internet]. Seattle: University of Washington; 1993–2026. Published on 19 Dec 2003; comprehensive update on 7 Aug 2025. NBK1146. PMID:20301325.
2. Orphanet. Malignant hyperthermia of anesthesia. ORPHA:423; Central core disease ORPHA:597; Multiminicore myopathy ORPHA:598; King-Denborough syndrome ORPHA:99741; Native American myopathy ORPHA:168572; Exercise-induced malignant hyperthermia ORPHA:466650 [Internet]. Data obtained through the public Orphanet interface (update of 2 Jul 2026). Disease entry. Accessed on 6 Oct 2026.
3. VariantValidator. HGVS validation and conversion to GRCh38 coordinates for transcripts NM_000540.3 (RYR1), NM_000069.3 (CACNA1S) and NM_145064.3 (STAC3) [Internet]. Validation service. Accessed on 6 Oct 2026.
4. Webb BD, Manoli I, Jabs EW. STAC3 disorder. In: GeneReviews® [Internet]. Seattle: University of Washington; published on 20 Jun 2019. NBK542808. PMID:31219695.
5. Glahn KPE, Girard T, Hellblom A, Hopkins PM, Johannsen S, Rüffert H, et al. Recognising and managing a malignant hyperthermia crisis: European Malignant Hyperthermia Group guideline v2024, including boxes 1 and 2 and the Delphi process [Internet]. Published on 4 Nov 2024; abridged version in Br J Anaesth. 2025;134(1):221–3. EMHG text. doi:10.1016/j.bja.2024.09.022. PMID:39482150. Accessed on 6 Oct 2026.
6. European Malignant Hyperthermia Group. Use of Penthrox (methoxyflurane) [Internet]. Published on 6 Jan 2025. Recommendation. Accessed on 6 Oct 2026.
7. Ibarra Moreno CA, Hu S, Kraeva N, Schuster F, Johannsen S, Rueffert H, et al. An assessment of penetrance and clinical expression of malignant hyperthermia in individuals carrying diagnostic ryanodine receptor 1 gene mutations. Anesthesiology. 2019;131(5):983–91. doi:10.1097/ALN.0000000000002813. PMID:31206373. PMC9912949.
8. Johnston JJ, Dirksen RT, Girard T, Hopkins PM, Kraeva N, Ognoon M, et al. Updated variant curation expert panel criteria and pathogenicity classifications for 251 variants for RYR1-related malignant hyperthermia susceptibility. Hum Mol Genet. 2022;31(23):4087–93. doi:10.1093/hmg/ddac145. PMID:35849058. PMC9703808.
9. Rüffert H, Gillies R, Hopkins PM, Glahn KPE, Johannsen S, Kamsteeg EJ, et al. European Malignant Hyperthermia Group 2025 guidelines for the investigation of malignant hyperthermia susceptibility. Br J Anaesth. 2026;136(2):653–61. doi:10.1016/j.bja.2025.11.006. PMID:41478797. Published online on 31 Dec 2025. Corrigendum (group membership list): Br J Anaesth. 2026;137(4):1326–7. doi:10.1016/j.bja.2026.06.048. PMID:42613200. Full text and figures accessed on 6 Oct 2026.
10. Malignant Hyperthermia Association of the United States. Managing an MH crisis [Internet]. Emergency protocol. Accessed on 6 Oct 2026.
11. Rüffert H, Bastian B, Bendixen D, Girard T, Heiderich S, Hellblom A, et al. Consensus guidelines on perioperative management of malignant hyperthermia suspected or susceptible patients from the European Malignant Hyperthermia Group. Br J Anaesth. 2021;126(1):120–30. doi:10.1016/j.bja.2020.09.029. PMID:33131754.
12. Gonsalves SG, Dirksen RT, Sangkuhl K, Pulk R, Alvarellos M, Vo T, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for the use of potent volatile anesthetic agents and succinylcholine in the context of RYR1 or CACNA1S genotypes. Clin Pharmacol Ther. 2019;105(6):1338–44. doi:10.1002/cpt.1319. PMID:30499100. PMC6513720.
13. Lawal TA, Todd JJ, Witherspoon JW, Bönnemann CG, Dowling JJ, Hamilton SL, et al. Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature. Skelet Muscle. 2020;10(1):32. doi:10.1186/s13395-020-00243-4. PMID:33190635. PMC7667763.
14. Riazi S, Watt S, Plester J, Biesecker LG. A proposed North American approach for genetic testing of individuals at risk for malignant hyperthermia. Anesthesiology. 2026;144(4):776–83. doi:10.1097/ALN.0000000000005849. PMID:41805301. PMC12965816.
15. van den Bersselaar LR, Heytens L, Silva HCA, Reimann J, Tasca G, Díaz-Cambronero Ó, et al. European Neuromuscular Centre consensus statement on anaesthesia in patients with neuromuscular disorders. Eur J Neurol. 2022;29(12):3486–507. doi:10.1111/ene.15526. PMID:35971866. PMC9826444.
16. European Reference Network for Rare Neuromuscular Diseases (ERN EURO-NMD) [Internet]. Network website. Accessed on 6 Oct 2026.
17. European Malignant Hyperthermia Group. MH units map [Internet]. Unit map. Accessed on 6 Oct 2026.
18. Denborough MA, Lovell RRH. Anaesthetic deaths in a family. Lancet. 1960;276(7140):45. doi:10.1016/S0140-6736(60)92690-8.
19. Denborough MA, Forster JF, Lovell RR, Maplestone PA, Villiers JD. Anaesthetic deaths in a family. Br J Anaesth. 1962;34(6):395–6. doi:10.1093/bja/34.6.395. PMID:13885389.
20. King JO, Denborough MA. Anesthetic-induced malignant hyperpyrexia in children. J Pediatr. 1973;83(1):37–40. doi:10.1016/S0022-3476(73)80309-9. PMID:4149045.
21. Dowling JJ, Lillis S, Amburgey K, Zhou H, Al-Sarraj S, Buk SJ, et al. King-Denborough syndrome with and without mutations in the skeletal muscle ryanodine receptor (RYR1) gene. Neuromuscul Disord. 2011;21(6):420–7. doi:10.1016/j.nmd.2011.03.006. PMID:21514828.
22. Harrison GG. Control of the malignant hyperpyrexic syndrome in MHS swine by dantrolene sodium. Br J Anaesth. 1975;47(1):62–5. doi:10.1093/bja/47.1.62. PMID:1148076.
23. Kolb ME, Horne ML, Martz R. Dantrolene in human malignant hyperthermia. Anesthesiology. 1982;56(4):254–62. doi:10.1097/00000542-198204000-00005. PMID:7039419.
24. MacLennan DH, Duff C, Zorzato F, Fujii J, Phillips M, Korneluk RG, et al. Ryanodine receptor gene is a candidate for predisposition to malignant hyperthermia. Nature. 1990;343(6258):559–61. doi:10.1038/343559a0. PMID:1967823.
25. McCarthy TV, Healy JM, Heffron JJ, Lehane M, Deufel T, Lehmann-Horn F, et al. Localization of the malignant hyperthermia susceptibility locus to human chromosome 19q12-13.2. Nature. 1990;343(6258):562–4. doi:10.1038/343562a0. PMID:2300206.
26. Fujii J, Otsu K, Zorzato F, de Leon S, Khanna VK, Weiler JE, et al. Identification of a mutation in porcine ryanodine receptor associated with malignant hyperthermia. Science. 1991;253(5018):448–51. doi:10.1126/science.1862346. PMID:1862346.
27. Gillard EF, Otsu K, Fujii J, Khanna VK, de Leon S, Derdemezi J, et al. A substitution of cysteine for arginine 614 in the ryanodine receptor is potentially causative of human malignant hyperthermia. Genomics. 1991;11(3):751–5. doi:10.1016/0888-7543(91)90084-R. PMID:1774074.
28. Monnier N, Procaccio V, Stieglitz P, Lunardi J. Malignant-hyperthermia susceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. Am J Hum Genet. 1997;60(6):1316–25. doi:10.1086/515454. PMID:9199552. PMC1716149.
29. Horstick EJ, Linsley JW, Dowling JJ, Hauser MA, McDonald KK, Ashley-Koch A, et al. Stac3 is a component of the excitation-contraction coupling machinery and mutated in Native American myopathy. Nat Commun. 2013;4:1952. doi:10.1038/ncomms2952. PMID:23736855. PMC4056023.
30. Magee KR, Shy GM. A new congenital non-progressive myopathy. Brain. 1956;79(4):610–21. doi:10.1093/brain/79.4.610. PMID:13396066.
31. Wu S, Ibarra MC, Malicdan MC, Murayama K, Ichihara Y, Kikuchi H, et al. Central core disease is due to RYR1 mutations in more than 90% of patients. Brain. 2006;129(Pt 6):1470–80. doi:10.1093/brain/awl077. PMID:16621918.
32. Ibarra Moreno CA, Silva HCA, Voermans NC, Jungbluth H, van den Bersselaar LR, Rendu J, et al. Myopathic manifestations across the adult lifespan of patients with malignant hyperthermia susceptibility: a narrative review. Br J Anaesth. 2024;133(4):759–67. doi:10.1016/j.bja.2024.05.046. PMID:39107166. PMC11443134.
33. Kushnir A, Todd JJ, Witherspoon JW, Yuan Q, Reiken S, Lin H, et al. Intracellular calcium leak as a therapeutic target for RYR1-related myopathies. Acta Neuropathol. 2020;139(6):1089–104. doi:10.1007/s00401-020-02150-w. PMID:32236737. PMC7788518.
34. National Center for Biotechnology Information. ClinVar: variant classifications for RYR1, CACNA1S and STAC3, records VCV000012964, VCV000012973, VCV000012970, VCV000012972, VCV000478235, VCV000017626, VCV000088744 and VCV001065119 [Internet]. ClinVar. Accessed on 6 Oct 2026.
35. European Malignant Hyperthermia Group. (Likely) pathogenic MH mutations: list of diagnostic RYR1 and CACNA1S variants, with change log since May 2025 and update of 25 Mar 2026 [Internet]. Variant list. Accessed on 6 Oct 2026.
36. Dlamini N, Voermans NC, Lillis S, Stewart K, Kamsteeg EJ, Drost G, et al. Mutations in RYR1 are a common cause of exertional myalgia and rhabdomyolysis. Neuromuscul Disord. 2013;23(7):540–8. doi:10.1016/j.nmd.2013.03.008. PMID:23628358.
37. Sambuughin N, Capacchione J, Blokhin A, Bayarsaikhan M, Bina S, Muldoon S. The ryanodine receptor type 1 gene variants in African American men with exertional rhabdomyolysis and malignant hyperthermia susceptibility. Clin Genet. 2009;76(6):564–8. doi:10.1111/j.1399-0004.2009.01251.x. PMID:19807743.
38. Fridriksdottir R, Jonsson AJ, Jensson BO, Sverrisson KO, Arnadottir GA, Skarphedinsdottir SJ, et al. Sequence variants in malignant hyperthermia genes in Iceland: classification and actionable findings in a population database. Eur J Hum Genet. 2021;29(12):1819–24. doi:10.1038/s41431-021-00954-2. PMID:34462577. PMC8633338.
39. Gener B, Burns JM, Griffin S, Boyer EW. Administration of ondansetron is associated with lethal outcome. Pediatrics. 2010;125(6):e1514–7. doi:10.1542/peds.2009-2795. PMID:20439600.
40. Zaharieva IT, Sarkozy A, Munot P, Manzur A, O'Grady G, Rendu J, et al. STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility. Hum Mutat. 2018;39(12):1980–94. doi:10.1002/humu.23635. PMID:30168660.
41. Johnston JJ, Dirksen RT, Girard T, Gonsalves SG, Hopkins PM, Riazi S, et al. Variant curation expert panel recommendations for RYR1 pathogenicity classifications in malignant hyperthermia susceptibility. Genet Med. 2021;23(7):1288–95. doi:10.1038/s41436-021-01125-w. PMID:33767344. PMC8263483.
42. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–24. doi:10.1038/gim.2015.30. PMID:25741868. PMC4544753.
43. Ying EZ, Douglass A, Hawari MA, Groom L, Stowell K, Dirksen RT, et al. Calibrating a functional assay for variant classification in RYR1-related malignant hyperthermia susceptibility. Hum Mol Genet. 2025;34(11):945–51. doi:10.1093/hmg/ddaf038. PMID:40192509. PMC13031167.
44. Malicdan MCV, Nishino I. Central core disease — retired chapter, for historical reference only. In: GeneReviews® [Internet]. Seattle: University of Washington; published on 16 May 2007, updated on 4 Dec 2014. PMID:20301565.
45. Beggs AH, Agrawal PB. Multiminicore disease — retired chapter, for historical reference only. In: GeneReviews® [Internet]. Seattle: University of Washington; published on 25 Mar 2003, updated on 24 Jan 2013. PMID:20301467.
46. Miller DM, Daly C, Aboelsaod EM, Gardner L, Hobson SJ, Riasat K, et al. Genetic epidemiology of malignant hyperthermia in the UK. Br J Anaesth. 2018;121(4):944–52. doi:10.1016/j.bja.2018.06.028. PMID:30236257. PMC6208294.
47. Firth HV, Hurst JA. Sensitivity to anaesthetic agents. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 524–5.
48. Orphanet. King-Denborough syndrome. ORPHA:99741 [Internet]. Definition obtained through the public Orphanet interface. Disease entry. Accessed on 6 Oct 2026.
49. Stamm DS, Aylsworth AS, Stajich JM, Kahler SG, Thorne LB, Speer MC, et al. Native American myopathy: congenital myopathy with cleft palate, skeletal anomalies, and susceptibility to malignant hyperthermia. Am J Med Genet A. 2008;146A(14):1832–41. doi:10.1002/ajmg.a.32370. PMID:18553514.
50. McKie AB, Alsaedi A, Vogt J, Stuurman KE, Weiss MM, Shakeel H, et al. Germline mutations in RYR1 are associated with foetal akinesia deformation sequence/lethal multiple pterygium syndrome. Acta Neuropathol Commun. 2014;2:148. doi:10.1186/s40478-014-0148-0. PMID:25476234. PMC4271450.
51. Firth HV, Hurst JA. Fetal akinesia. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 724–5.
52. Larach MG, Gronert GA, Allen GC, Brandom BW, Lehman EB. Clinical presentation, treatment, and complications of malignant hyperthermia in North America from 1987 to 2006. Anesth Analg. 2010;110(2):498–507. doi:10.1213/ANE.0b013e3181c6b9b2. PMID:20081135.
53. Riazi S, van den Bersselaar LR, Islander G, Heytens L, Snoeck MMJ, Bjorksten A, et al. Pre-operative exercise and pyrexia as modifying factors in malignant hyperthermia (MH). Neuromuscul Disord. 2022;32(8):628–34. doi:10.1016/j.nmd.2022.06.003. PMID:35738978.
54. Burkman JM, Posner KL, Domino KB. Analysis of the clinical variables associated with recrudescence after malignant hyperthermia reactions. Anesthesiology. 2007;106(5):901–6. doi:10.1097/01.anes.0000265148.86566.68. PMID:17457120.
55. European Medicines Agency. Agilus (dantrolene sodium hemiheptahydrate) 120 mg: summary of product characteristics and European public assessment report. Authorisation of 29 May 2024 [Internet]. EPAR; product information. Accessed on 6 Oct 2026.
56. Glahn KPE, Bendixen D, Girard T, Hopkins PM, Johannsen S, Rüffert H, et al. Availability of dantrolene for the management of malignant hyperthermia crises: European Malignant Hyperthermia Group guidelines. Br J Anaesth. 2020;125(2):133–40. doi:10.1016/j.bja.2020.04.089. PMID:32591088.
57. Larach MG, Dirksen SJ, Belani KG, Brandom BW, Metz KM, Policastro MA, et al. Creation of a guide for the transfer of care of the malignant hyperthermia patient from ambulatory surgery centers to receiving hospital facilities. Anesth Analg. 2012;114(1):94–100. doi:10.1213/ANE.0b013e3182373b4a. PMID:22052978.
58. Wappler F, Fiege M, Steinfath M, Agarwal K, Scholz J, Singh S, et al. Evidence for susceptibility to malignant hyperthermia in patients with exercise-induced rhabdomyolysis. Anesthesiology. 2001;94(1):95–100. doi:10.1097/00000542-200101000-00019. PMID:11135728.
59. Kraeva N, Sapa A, Dowling JJ, Riazi S. Malignant hyperthermia susceptibility in patients with exertional rhabdomyolysis: a retrospective cohort study and updated systematic review. Can J Anaesth. 2017;64(7):736–43. doi:10.1007/s12630-017-0865-5. PMID:28326467.
60. Kruijt N, Laforet P, Vissing J, Bhai S, Stemmerik MG, Kleefeld F, et al. 276th ENMC International Workshop: recommendations on optimal diagnostic pathway and management strategy for patients with acute rhabdomyolysis worldwide. Neuromuscul Disord. 2025;50:105344. doi:10.1016/j.nmd.2025.105344. PMID:40220353.
61. Kruijt N, van de Camp SAJH, Kramer JJ, van den Bersselaar LR, Schouten M, Gardeitchik T, et al. Rhabdomyolysis in the era of next-generation sequencing: selecting patients with a high likelihood of a genetic susceptibility using 'RHABDO' features. Genes (Basel). 2025;16(9):995. doi:10.3390/genes16090995. PMID:41009941. PMC12470204.
62. van den Bersselaar LR, Kruijt N, Kamsteeg EJ, Fernandez-Garcia MA, Treves S, Yang CY, et al. Patient-reported symptoms, fatigue, functional impairment and quality of life in RYR1-related malignant hyperthermia and exertional rhabdomyolysis. Neuromuscul Disord. 2026;67:107373. doi:10.1016/j.nmd.2026.107373. PMID:42617308.
63. Campos IFS, Ribeiro EM. Miopatias congênitas. In: Ribeiro EM, coord. Síndromes Genéticas: Reconhecer para Tratar. Fortaleza: EdUnichristus; 2021. Chapter 15, section 15.3, p. 285–8.
64. Schade van Westrum SM, Wahbi K, Bonne G, van der Kooi AJ. Hereditary neuromuscular diseases and cardiac involvement. In: Baars HF, van der Smagt JJ, Doevendans PAFM, van Tintelen JP, editors. Clinical Cardiogenetics. 3rd ed. Cham: Springer; 2020. Chapter 22, p. 377 and 382. doi:10.1007/978-3-030-45457-9_22.
65. Hopkins PM, Rüffert H, Snoeck MM, Girard T, Glahn KPE, Ellis FR, et al. European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility. Br J Anaesth. 2015;115(4):531–9. doi:10.1093/bja/aev225. PMID:26188342. Full text provided by the EMHG.
66. Larach MG, Localio AR, Allen GC, Denborough MA, Ellis FR, Gronert GA, et al. A clinical grading scale to predict malignant hyperthermia susceptibility. Anesthesiology. 1994;80(4):771–9. doi:10.1097/00000542-199404000-00008. PMID:8024130.
67. Pardessus P, Bruneau B, Lagarde M, Maroun Y, Roux Buisson N, Faure J, et al. Malignant hyperthermia in France: characteristics of 93 diagnosed patients in one French reference centre: a retrospective data analysis. Eur J Anaesthesiol. 2026. doi:10.1097/EJA.0000000000002444. PMID:42290216.
68. Hellblom A, Soller M, Samuelsson C. Malignant hyperthermia in Sweden: clinical presentations and genetic findings. Acta Anaesthesiol Scand. 2026;70(6):e70255. doi:10.1111/aas.70255. PMID:42126337. PMC13170511.
69. Allen GC, Larach MG, Kunselman AR. The sensitivity and specificity of the caffeine-halothane contracture test: a report from the North American Malignant Hyperthermia Registry. Anesthesiology. 1998;88(3):579–88. doi:10.1097/00000542-199803000-00006. PMID:9523799.
70. European Malignant Hyperthermia Group. STAC3 variants in susceptibility to malignant hyperthermia [Internet]. Group statement. Accessed on 6 Oct 2026.
71. Yu KD, Betts MN, Urban GM, Schwartz MLB, Robinson TO, Moyer RJ, et al. Evaluation of malignant hyperthermia features in patients with pathogenic or likely pathogenic RYR1 variants disclosed through a population genomic screening program. Anesthesiology. 2024;140(1):52–61. doi:10.1097/ALN.0000000000004786. PMID:37787745.
72. Lee K, Abul-Husn NS, Amendola LM, Brothers KB, Chung WK, Gollob MH, et al. ACMG SF v3.3 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2025;27(8):101454. doi:10.1016/j.gim.2025.101454. PMID:40568962. PMC12318660.
73. Snoeck MMJ, Gillies R, Almeida da Silva HC, Rüffert H, Girard T, Hellblom A, et al. Consensus guideline from the European Malignant Hyperthermia Group on perioperative management of patients with an inherited primary disorder of skeletal muscle. Br J Anaesth. 2026;137(3):721–31. doi:10.1016/j.bja.2026.06.011. PMID:42532738.
74. Jones KL, Jones MC, del Campo M. Noonan syndrome. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 148.
75. Jones KL, Jones MC, del Campo M. Schwartz-Jampel syndrome. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 304.
76. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Schwartz-Jampel syndrome (MIM 255800). In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 199–204.
77. Jones KL, Jones MC, del Campo M. Larsen syndrome. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 604.
78. Firth HV, Hurst JA. Arthrogryposis. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 69.
79. Orphanet. Multiple pterygium-malignant hyperthermia syndrome. ORPHA:2215 [Internet]. Definition obtained through the public Orphanet interface. Disease entry. Accessed on 6 Oct 2026.
80. Jaeken J, Morava E. Congenital Disorders of Glycosylation, Dolichol and Glycosylphosphatidylinositol Metabolism. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 43, section 43.4.4 (COG6-CDG). doi:10.1007/978-3-662-63123-2_43.
81. Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 1, Clinical approach to inborn errors of metabolism in paediatrics, section 1.4.8.3.
82. U.S. Food and Drug Administration. Dantrium Intravenous (dantrolene sodium for injection), NDA 018264: prescribing information, current version dated 10 Mar 2026 [Internet]. DailyMed. Accessed on 6 Oct 2026.
83. U.S. Food and Drug Administration. Ryanodex (dantrolene sodium) injectable suspension, NDA 205579: prescribing information, version of 30 Oct 2024 [Internet]. DailyMed. Accessed on 6 Oct 2026.
84. Malignant Hyperthermia Association of the United States. Frequently asked questions about dantrolene and stocking an MH cart [Internet]. Frequently asked questions. Accessed on 6 Oct 2026.
85. Tsutsumi YM, Nagasaka H, Mukaida K, Ichihara Y, Yasuda T, Miyoshi H, et al. JSA guideline for management of malignant hyperthermia in 2025. J Anesth. 2026;40(1):4–12. doi:10.1007/s00540-025-03647-y. PMID:41504952. PMC12860801.
86. European Medicines Agency, Committee for Medicinal Products for Human Use. Positive opinion on Agilus, 21 Mar 2024 [Internet]. Opinion summary. Accessed on 6 Oct 2026.
87. Brandom BW, Larach MG, Chen MS, Young MC. Complications associated with the administration of dantrolene 1987 to 2006: a report from the North American Malignant Hyperthermia Registry of the Malignant Hyperthermia Association of the United States. Anesth Analg. 2011;112(5):1115–23. doi:10.1213/ANE.0b013e31820b5f1f. PMID:21372281. PMC3498049.
88. U.S. Food and Drug Administration. Dantrium (dantrolene sodium) capsules, NDA 017443: prescribing information with a boxed hepatotoxicity warning, version of 21 Aug 2026 [Internet]. openFDA. Accessed on 6 Oct 2026.
89. Norgine Pharmaceuticals Ltd. Dantrium Intravenous 20 mg: summary of product characteristics, PL 20011/0034, first authorisation on 14 Feb 1980, text revised on 11 Mar 2025 [Internet]. electronic Medicines Compendium. Accessed on 6 Oct 2026.
90. European Medicines Agency. Orphan drug designation EU/3/14/1379, dantrolene sodium, 19 Nov 2014 [Internet]. Orphan designation. Accessed on 6 Oct 2026.
91. Norgine Pharmaceuticals Ltd. Agilus 120 mg: summary of product characteristics, PLGB 20011/0075, first authorisation on 8 Jul 2024 [Internet]. electronic Medicines Compendium. Accessed on 6 Oct 2026.
92. Cristália Produtos Químicos Farmacêuticos Ltda. Dantrolen (dantrolene sodium) lyophilised powder for solution for injection, registration MS 1.0298.0206: package leaflet for healthcare professionals [Internet]. Package leaflet. Accessed on 6 Oct 2026.
93. INFARMED — Autoridade Nacional do Medicamento e Produtos de Saúde. Public assessment report on public reimbursement of Agilus (dantrolene), favourable decision of 30 Sep 2025, report of 21 Oct 2025 [Internet]. Report. Accessed on 6 Oct 2026.
94. Agence nationale de sécurité du médicament et des produits de santé. Lettre aux professionnels de santé: Agilus 120 mg et Dantrium IV 20 mg, 1 Sep 2025 [Internet]. Communication. Accessed on 6 Oct 2026.
95. Health Canada. Supply notice: dantrolene sodium injection, published on 21 Jul 2025 and updated on 1 Apr 2026 [Internet]. Supply notice. Accessed on 6 Oct 2026.
96. Ontario Poison Centre. Dantrolene shortage 2026 [Internet]. Notice. Accessed on 6 Oct 2026.
97. Therapeutic Goods Administration (Australia). Medicine shortage report: Dantrium 20 mg, shortage between 3 Jul and 25 Aug 2026 [Internet]. Shortage database. Accessed on 6 Oct 2026.
98. European Malignant Hyperthermia Group. Perioperative management of MH suspected or susceptible patients: anaesthetic management [Internet]. Published on 27 Feb 2018. Recommendation. Accessed on 6 Oct 2026.
99. European Malignant Hyperthermia Group. Preparation of anaesthetic workstations for MH suspected or susceptible patients [Internet]. Published on 27 Feb 2018. Recommendation. Accessed on 6 Oct 2026.
100. European Malignant Hyperthermia Group. Occupational exposure to volatile anaesthetics [Internet]. Published on 28 Jul 2020. Recommendation. Accessed on 6 Oct 2026.
101. European Malignant Hyperthermia Group. Malignant hyperthermia during pregnancy [Internet]. Published on 20 May 2019, revised on 26 May 2026. Recommendation. Accessed on 6 Oct 2026.
102. European Medicines Agency. Bridion (sugammadex) 100 mg/mL: summary of product characteristics. First authorisation on 25 Jul 2008, last renewal on 21 Jun 2013 [Internet]. Product information. Accessed on 26 Oct 2026.
103. U.S. Food and Drug Administration. Bridion (sugammadex) injection: prescribing information, version of 18 Dec 2025 [Internet]. openFDA. Accessed on 26 Oct 2026.
104. U.S. Food and Drug Administration. Rocuronium bromide injection (Fresenius Kabi), NDA 217472: prescribing information, version of 2 Aug 2026 [Internet]. openFDA. Accessed on 26 Oct 2026.
105. Todd JJ, Lawal TA, Witherspoon JW, Chrismer IC, Razaqyar MS, Punjabi M, et al. Randomized controlled trial of N-acetylcysteine therapy for RYR1-related myopathies. Neurology. 2020;94(13):e1434–44. doi:10.1212/WNL.0000000000008872. PMID:31941795. PMC7274912.
106. Todd JJ, Lawal TA, Chrismer IC, Kokkinis A, Grunseich C, Jain MS, et al. Rycal S48168 (ARM210) for RYR1-related myopathies: a phase one, open-label, dose-escalation trial. EClinicalMedicine. 2024;68:102433. doi:10.1016/j.eclinm.2024.102433. PMID:38318125. PMC10839573.
107. ClinicalTrials.gov. Phase 2 trial of S48168 (ARM210) in adults with autosomal dominant RYR1-related myopathy, NCT07560020 [Internet]. Trial registry. Accessed on 6 Oct 2026.
108. ClinicalTrials.gov. COMPIS: open-label crossover trial of oral salbutamol in congenital myopathies, NCT05099107 [Internet]. Trial registry. Accessed on 6 Oct 2026.
109. ARMGO Pharma. Press release on phase 1b results of Rycal S48168 (ARM210) [Internet]. 29 Jan 2024. Announcement. Accessed on 6 Oct 2026.
110. Raga S, Voermans N, Perez-Neri I, Dowling J, Jungbluth H, Baranello G, et al. Treatments for RYR1-related disorders. Cochrane Database Syst Rev. 2024;12:CD014439. doi:10.1002/14651858.CD014439. PMID:39655671. PMC11629463.
111. ClinicalTrials.gov. Ryanodex in exertional heat stroke, phase 2 study, NCT02513095 [Internet]. Trial registry. Accessed on 6 Oct 2026.
112. ClinicalTrials.gov. Ryanodex in exertional heat stroke, phase 3 study, NCT03600376 [Internet]. Trial registry. Accessed on 6 Oct 2026.
113. Medthority. Complete response letter for Ryanodex to treat exertional heat stroke — reported sponsor announcement, Aug 2020 [Internet]. News item. Accessed on 6 Oct 2026.
114. Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Al Turki S, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48(2):126–33. doi:10.1038/ng.3469. PMID:26656846. PMC4731925.
115. European Malignant Hyperthermia Group. Life insurance and MH [Internet]. Published on 28 Sep 2023, updated on 9 May 2024. Recommendation. Accessed on 6 Oct 2026.
116. Brady JE, Sun LS, Rosenberg H, Li G. Prevalence of malignant hyperthermia due to anesthesia in New York State, 2001–2005. Anesth Analg. 2009;109(4):1162–6. doi:10.1213/ANE.0b013e3181ac1548. PMID:19762744.
117. Rosero EB, Adesanya AO, Timaran CH, Joshi GP. Trends and outcomes of malignant hyperthermia in the United States, 2000 to 2005. Anesthesiology. 2009;110(1):89–94. doi:10.1097/ALN.0b013e318190bb08. PMID:19104175.
118. Gonsalves SG, Ng D, Johnston JJ, Teer JK, Stenson PD, Cooper DN, et al. Using exome data to identify malignant hyperthermia susceptibility mutations. Anesthesiology. 2013;119(5):1043–53. doi:10.1097/ALN.0b013e3182a8a8e7. PMID:24195946. PMC4077354.
119. Mungunsukh O, Deuster P, Muldoon S, O'Connor F, Sambuughin N. Estimating prevalence of malignant hyperthermia susceptibility through population genomics data. Br J Anaesth. 2019;123(5):e461–3. doi:10.1016/j.bja.2019.06.010. PMID:31301762.
120. Kelly MA, Leader JB, Wain KE, Bodian D, Oetjens MT, Ledbetter DH, et al. Leveraging population-based exome screening to impact clinical care: the evolution of variant assessment in the Geisinger MyCode research project. Am J Med Genet C Semin Med Genet. 2021;187(1):83–94. doi:10.1002/ajmg.c.31887. PMID:33576083.
121. Efremova E, Baranova E, Esibov A, Rozhkova A, Rutkovskaya E, Krupinova J, et al. Estimating the prevalence of malignant hyperthermia susceptibility based on causative RYR1 and CACNA1S variants. Int J Mol Sci. 2026;27(18):8327. doi:10.3390/ijms27188327. PMID:42794754. PMC13607192.
122. Telegrafi A, Webb BD, Robbins SM, Speck-Martins CE, FitzPatrick D, Fleming L, et al. Identification of STAC3 variants in non-Native American families with overlapping features of Carey-Fineman-Ziter syndrome and Moebius syndrome. Am J Med Genet A. 2017;173(10):2763–71. doi:10.1002/ajmg.a.38375. PMID:28777491. PMC5843189.
123. Kossugue PM, Paim JF, Navarro MM, Silva HC, Pavanello RC, Gurgel-Giannetti J, et al. Central core disease due to recessive mutations in RYR1 gene: is it more common than described? Muscle Nerve. 2007;35(5):670–4. doi:10.1002/mus.20715. PMID:17226826.
124. Gomes GRF, Mariano TC, Braga VLL, Ribeiro EM, Guimarães IP, Pereira KSAF, et al. Bailey-Bloch congenital myopathy in Brazilian patients: a very rare myopathy with malignant hyperthermia susceptibility. Brain Sci. 2023;13(8):1184. doi:10.3390/brainsci13081184. PMID:37626540. PMC10452826.
125. Edwards CM, Jenkins TK, Gravenstein N, Gunnett AM, Martin TW. Genetically confirmed malignant hyperthermia in a six-week-old infant: a case report. Cureus. 2022;14(7):e27010. doi:10.7759/cureus.27010. PMID:35989752. PMC9387088.
126. Nelson P, Litman RS. Malignant hyperthermia in children: an analysis of the North American Malignant Hyperthermia Registry. Anesth Analg. 2014;118(2):369–74. doi:10.1213/ANE.0b013e3182a8fad0. PMID:24299931.
127. RYR-1 Foundation [Internet]. Patient organisation. Accessed on 6 Oct 2026.